ORCID Profile
0000-0002-0302-5727
Current Organisations
University of Melbourne
,
Monash University
,
Florey Institute of Neuroscience and Mental Health
,
Alfred Health
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Publisher: Cold Spring Harbor Laboratory
Date: 10-02-2023
DOI: 10.1101/2023.02.10.527924
Abstract: Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2 -linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP-43 and ubiquilin 2 to disease pathogenesis remain largely under-characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three UBQLN2 p.T487I-linked ALS/FTD cases, three non- UBQLN2 -linked (sporadic) ALS cases, and eight non-neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP-43 aggregates, and aggregates containing both proteins in regions of interest to determine how UBQLN2 -linked and non- UBQLN2 -linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP-43 are predominantly small and punctate, and are abundant in the hippoc al formation, spinal cord, all tested regions of neocortex, medulla, and substantia nigra in UBQLN2 -linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to UBQLN2 -linked ALS/FTD. While ubiquilin 2 deposition in frontotemporal regions may enhance cognitive risk in UBQLN2 -linked cases, ubiquilin 2 is deposited mainly in clinically unaffected regions throughout the CNS such that overall symptomology in these cases maps best to the aggregation of TDP-43.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2018
DOI: 10.1038/S41467-018-05325-Y
Abstract: Genetic, epigenetic, and environmental factors contribute to the multifactorial disorder progressive supranuclear palsy (PSP). Here, we study epigenetic changes by genome-wide analysis of DNA from postmortem tissue of forebrains of patients and controls and detect significant ( P 0.05) methylation differences at 717 CpG sites in PSP vs. controls. Four-hundred fifty-one of these sites are associated with protein-coding genes. While differential methylation only affects a few sites in most genes, DLX1 is hypermethylated at multiple sites. Expression of an antisense transcript of DLX1 , DLX1AS , is reduced in PSP brains. The amount of DLX1 protein is increased in gray matter of PSP forebrains. Pathway analysis suggests that DLX1 influences MAPT -encoded Tau protein. In a cell system, overexpression of DLX1 results in downregulation of MAPT while overexpression of DLX1AS causes upregulation of MAPT . Our observations suggest that altered DLX1 methylation and expression contribute to pathogenesis of PSP by influencing MAPT .
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6CC10066J
Abstract: Rhenium( i ) complexes of tridentate N-heterocyclic carbene ligands that bind to amyloid plaques in human brain tissue are reported.
Publisher: Wiley
Date: 04-10-2014
DOI: 10.1002/PROS.22895
Abstract: Phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in prostate carcinoma due to the loss of tumor suppressor PTEN, which leads to increased Akt activity. Expression of INPP4B, another negative regulator of the PI3K/Akt pathway, is also reduced in prostate carcinoma. However, uncertainty exists regarding the association of INPP4B expression and biochemical and clinical relapse of prostate carcinoma. INPP4B expression in benign prostate acini was analyzed by co-immunofluorescence with cytokeratins (CK) 5, 8, 19, androgen receptor (AR), c-MET, chromogranin A and Ki67. INPP4B expression in prostate carcinoma was analyzed in two independent cohorts (n = 406). The association of INPP4B with biochemical and clinical prostate carcinoma relapse was assessed by Kaplan-Meier and Cox proportional hazards modeling. INPP4B was expressed in luminal epithelium within benign ducts, and was highly expressed in CK5+/CK8+/CK19+/AR-/c-MET+/Ki67- intermediate cells in proliferative inflammatory atrophic acini. Overall, INPP4B expression was reduced in prostate carcinoma compared to benign epithelium. Absent/low INPP4B expression was associated with reduced biochemical relapse-free survival (P = 0.01) and increased risk of clinical relapse (P = 0.01). Absence of INPP4B expression was an independent predictor of clinical relapse free survival (P = 0.004) when modeled with Gleason score (P = 0.027) and pathologic stage (P = 0.07). INPP4B is highly expressed in intermediate cells within proliferative inflammatory atrophic ducts, and expression is reduced in prostate carcinoma. Absence of INPP4B expression is associated with poor outcome following radical prostatectomy, and represents an independent prognostic marker of prostate carcinoma clinical recurrence.
Publisher: Elsevier BV
Date: 2010
DOI: 10.4158/EP09177.CR
Publisher: Wiley
Date: 04-2006
DOI: 10.1111/J.1474-9726.2006.00200.X
Abstract: Transgenic mice carrying mutant Cu/Zn superoxide dismutase (SOD1) recapitulate the motor impairment of human amyotrophic lateral sclerosis (ALS). The amyloid-beta (Abeta) peptide associated with Alzheimer's disease is neurotoxic. To investigate the potential role of Abeta in ALS development, we generated a double transgenic mouse line that overexpresses SOD1(G93A) and amyloid precursor protein (APP)-C100. The transgenic mouse C100.SOD1(G93A) overexpresses Abeta and shows earlier onset of motor impairment but has the same lifespan as the single transgenic SOD1(G93A) mouse. To determine the mechanism associated with this early-onset phenotype, we measured copper and zinc levels in brain and spinal cord and found both significantly elevated in the single and double transgenic mice compared with their littermate control mice. Increased glial fibrillary acidic protein and decreased APP levels in the spinal cord of C100.SOD1(G93A) mice compared with the SOD1(G93A) mice agree with the neuronal damage observed by immunohistochemical analysis. In the spinal cords of C100.SOD1(G93A) double transgenic mice, soluble Abeta was elevated in mice at end-stage disease compared with the pre-symptomatic stage. Buffer-insoluble SOD1 aggregates were significantly elevated in the pre-symptomatic mice of C100.SOD1(G93A) compared with the age-matched SOD1(G93A) mice, correlating with the earlier onset of motor impairment in the C100.SOD1(G93A) mice. This study supports abnormal SOD1 protein aggregation as the pathogenic mechanism in ALS, and implicates a potential role for Abeta in the development of ALS by exacerbating SOD1(G93A) aggregation.
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.EJON.2006.10.007
Abstract: One of the main challenges of colorectal cancer follow-up is the detection of early disease in order to influence survival and improve outcome. Yet, the benefits of follow-up are not only related to survival. It is well documented that patients can experience an array of problems following colorectal cancer surgery which impact upon quality of life, therefore symptom management plays an important part in the overall spectrum of follow-up care. In addition, there is emerging evidence to suggest that clinical nurse specialists are well placed in the multidisciplinary team to co-ordinate such follow-up programmes. This paper reports on a pilot study designed to assess the feasibility of a follow-up programme led by nurse specialists for patients with colorectal cancer. Key outcome areas were adherence to an agreed follow-protocol, quality of life, patient and clinician satisfaction and a cost-analysis of the new model. The study was conducted over one year with 60 patients. This redesign resulted in a smoother pathway of follow-up care, improved quality of life and acceptance to both patients and clinicians alike. The introduction of a nurse-led follow-up model is expected to demonstrate cost savings over a 3 year rolling follow-up programme.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.NBD.2011.03.009
Abstract: BACE initiates the amyloidogenic processing of the amyloid precursor protein (APP) that results in the production of Aβ peptides associated with Alzheimer's disease (AD). Previous studies have indicated that BACE is elevated in the frontal cortex of AD patients. Golgi-localized γ-ear containing ADP ribosylation factor-binding proteins (GGA) control the cellular trafficking of BACE and may alter its levels. To investigate a link between BACE and GGA expression in AD, frontal cortex s les from AD (N = 20) and healthy, age-matched controls (HC, N =17) were analyzed by immunoblotting. After normalization to the neuronal marker β-tubulin III, the data indicate an average two-fold increase of BACE protein (p = 0.01) and a 64% decrease of GGA3 in the AD group compared to the HC (p = 0.006). GGA1 levels were also decreased in AD, but a statistical significance was not achieved. qRT-PCR analysis of GGA3 mRNA showed no difference between AD and HC. There was a strong correlation between GGA1 and GGA3 in both AD and HC, but no correlation between BACE and GGA levels. Subcellular fractionation of AD cortex with low levels of GGA proteins showed an alteration of BACE distribution and extensive co-localization with APP. These data suggest that altered compartmentalization of BACE in AD promotes the amyloidogenic processing of APP.
Publisher: Elsevier BV
Date: 05-2000
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.JVIROMET.2009.11.029
Abstract: JC polyomavirus (JCV) infects 80% of the population. In immunosuppressed patients viral replication may be enhanced, resulting in progressive multifocal leukoencephalopathy. There are at least eight distinct strains of JCV of which distribution varies between ethnic groups however there remain issues with identifying viral strains due to the insufficient yield and sensitivity of Sanger sequencing (SS) protocols. In this study matrix assisted laser desorption/ionisation time of flight mass spectrometry (MALDI TOF MS) is presented as an alternative to SS. DNA from 19 urine s les was assessed. Successful lification and strain identification was possible in all s les with >10 copies of starting material indicating a high sensitivity assay, in contrast to SS (>20 copies). The genotypes defined for each s le via MALDI TOF MS were identical where SS resulted in a readable trace. MALDI TOF MS identified eight novel SNPs in the VP1 gene. This study represents the first application of MALDI TOF MS to viral comparative sequence analysis.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2017
DOI: 10.1007/S00702-016-1625-3
Abstract: It has been suggest that drugs specifically targeting muscarinic receptors will be useful in treating Alzheimer's disease. We decided to determine if the response to such drugs may be altered, because of changes in the levels of muscarinic receptors in the CNS from subjects with the disorder. We used in situ radioligand binding with autoradiography to measure the levels of [
Publisher: Springer Science and Business Media LLC
Date: 25-11-2019
DOI: 10.1038/S41593-019-0539-4
Abstract: There is currently little information available about how in idual cell types contribute to Alzheimer's disease. Here we applied single-nucleus RNA sequencing to entorhinal cortex s les from control and Alzheimer's disease brains (n = 6 per group), yielding a total of 13,214 high-quality nuclei. We detail cell-type-specific gene expression patterns, unveiling how transcriptional changes in specific cell subpopulations are associated with Alzheimer's disease. We report that the Alzheimer's disease risk gene APOE is specifically repressed in Alzheimer's disease oligodendrocyte progenitor cells and astrocyte subpopulations and upregulated in an Alzheimer's disease-specific microglial subopulation. Integrating transcription factor regulatory modules with Alzheimer's disease risk loci revealed drivers of cell-type-specific state transitions towards Alzheimer's disease. For ex le, transcription factor EB, a master regulator of lysosomal function, regulates multiple disease genes in a specific Alzheimer's disease astrocyte subpopulation. These results provide insights into the coordinated control of Alzheimer's disease risk genes and their cell-type-specific contribution to disease susceptibility. These results are available at adsn.ddnetbio.com.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-05-2011
Publisher: Elsevier BV
Date: 05-2000
Publisher: Oxford University Press (OUP)
Date: 28-09-2023
DOI: 10.1093/BJD/LJAD365
Publisher: Springer Science and Business Media LLC
Date: 07-11-2017
Publisher: Springer Science and Business Media LLC
Date: 05-2007
DOI: 10.1203/PDR.0B013E318045BE20
Abstract: Inhaled nitric oxide (iNO) enhances ventilation in very preterm infants, but the effects on the brain remain uncertain. We evaluated the impact of iNO on brain growth and cerebral injury in a premature baboon model. Baboons were delivered at 125 d of gestation (term 185 d of gestation) and ventilated for 14 d with either positive pressure ventilation (PPV) (n = 7) or PPV + iNO (n = 8). Brains were assessed histologically for parameters of development and injury. Compared with gestational controls (n = 7), brain and body weights were reduced but brain-to-body weight ratios were increased in all prematurely delivered (PD) animals the surface folding index (SFI), was reduced in PPV but not PPV + iNO animals. Compared with controls, the brain damage index was increased (p < 0.05) in both cohorts of PD animals. There was no difference between ventilatory regimens, however, in 25% of animals with iNO therapy, there were organized hematomas in the subarachnoid space. Overall, iNO did not alter the extent of brain damage but did result in the presence of hematomas. These results do not confirm any protective or major injurious effect of nitric oxide therapy on the developing brain.
Publisher: Springer Science and Business Media LLC
Date: 19-06-2020
DOI: 10.1038/S41467-020-16819-Z
Abstract: MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl D139V , that alters the two-helix ‘brace’ that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl D139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).
Publisher: Oxford University Press (OUP)
Date: 29-12-2018
DOI: 10.1111/BJD.15855
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2019
DOI: 10.1101/628347
Abstract: Alzheimer’s disease (AD) is a heterogeneous disease that is largely dependent on the complex cellular microenvironment in the brain. This complexity impedes our understanding of how in idual cell types contribute to disease progression and outcome. To characterize the molecular and functional cell ersity in the human AD brain we utilized single nuclei RNA- seq in AD and control patient brains in order to map the landscape of cellular heterogeneity in AD. We detail gene expression changes at the level of cells and cell subclusters, highlighting specific cellular contributions to global gene expression patterns between control and Alzheimer’s patient brains. We observed distinct cellular regulation of APOE which was repressed in oligodendrocyte progenitor cells (OPCs) and astrocyte AD subclusters, and highly enriched in a microglial AD subcluster. In addition, oligodendrocyte and microglia AD subclusters show discordant expression of APOE. Integration of transcription factor regulatory modules with downstream GWAS gene targets revealed subcluster-specific control of AD cell fate transitions. For ex le, this analysis uncovered that astrocyte ersity in AD was under the control of transcription factor EB (TFEB), a master regulator of lysosomal function and which initiated a regulatory cascade containing multiple AD GWAS genes. These results establish functional links between specific cellular sub-populations in AD, and provide new insights into the coordinated control of AD GWAS genes and their cell-type specific contribution to disease susceptibility. Finally, we created an interactive reference web resource which will facilitate brain and AD researchers to explore the molecular architecture of subtype and AD-specific cell identity, molecular and functional ersity at the single cell level. We generated the first human single cell transcriptome in AD patient brains Our study unveiled 9 clusters of cell-type specific and common gene expression patterns between control and AD brains, including clusters of genes that present properties of different cell types (i.e. astrocytes and oligodendrocytes) Our analyses also uncovered functionally specialized sub-cellular clusters: 5 microglial clusters, 8 astrocyte clusters, 6 neuronal clusters, 6 oligodendrocyte clusters, 4 OPC and 2 endothelial clusters, each enriched for specific ontological gene categories Our analyses found manifold AD GWAS genes specifically associated with one cell-type, and sets of AD GWAS genes co-ordinately and differentially regulated between different brain cell-types in AD sub-cellular clusters We mapped the regulatory landscape driving transcriptional changes in AD brain, and identified transcription factor networks which we predict to control cell fate transitions between control and AD sub-cellular clusters Finally, we provide an interactive web-resource that allows the user to further visualise and interrogate our dataset. Data resource web interface : adsn.ddnetbio.com
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.BURNS.2007.01.014
Abstract: Activin A is a member of the transforming growth factor-beta (TGF-beta) family of cytokines and growth factors and upregulation of this protein has been linked with a number of disease processes associated with chronic inflammation and fibrosis. Its potential involvement in burns has not yet been investigated. We therefore studied the localization of activin in tissue sections from excised mid- and deep dermal and full thickness cutaneous burn by immunohistochemistry. There was cell-specific temporal expression in tissues with prominent expression from day 4 onwards in lymphocytes and histiocytes and expression from day 8 onwards in reactive fibroblasts and endothelial cells. Immunopositivity over the first 18 days persisted in reactive fibroblasts and lymphocytes although the latter were in most circumstances decreasing in number. These data are consistent with activin A being central to the inflammatory and repair phases occurring in burnt skin and early scar formation. Modulation of activin expression and actions may, therefore, be a target for the management of burns.
Publisher: Korean Society for Molecular and Cellular Biology
Date: 31-07-2021
Publisher: Public Library of Science (PLoS)
Date: 23-08-2016
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.JOCN.2004.03.022
Abstract: Tanycytic ependymoma is a rare fibrillary variant of ependymoma with a predilection for the spinal cord. We present an unusual supratentorial subcortical tanycytic ependymoma in a 17-year old male presenting with seizures. Only two other cases of subcortical tanycytic ependymoma have been reported.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-05-2014
Publisher: Springer Science and Business Media LLC
Date: 18-04-2018
DOI: 10.1038/S41419-018-0491-3
Abstract: The role of astrocyte elevated gene-1 (AEG-1) in nigral dopaminergic (DA) neurons has not been studied. Here we report that the expression of AEG-1 was significantly lower in DA neurons in the postmortem substantia nigra of patients with Parkinson’s disease (PD) compared to age-matched controls. Similarly, decreased AEG-1 levels were found in the 6-hydroxydopamine (6-OHDA) mouse model of PD. An adeno-associated virus-induced increase in the expression of AEG-1 attenuated the 6-OHDA-triggered apoptotic death of nigral DA neurons. Moreover, the neuroprotection conferred by the AEG-1 upregulation significantly intensified the neurorestorative effects of the constitutively active ras homolog enriched in the brain [Rheb(S16H)]. Collectively, these results demonstrated that the sustained level of AEG-1 as an important anti-apoptotic factor in nigral DA neurons might potentiate the therapeutic effects of treatments, such as Rheb(S16H) administration, on the degeneration of the DA pathway that characterizes PD.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-10-2020
Abstract: Breast cancer is the most common cancer in women and metastasis remains the leading cause of death. P-Rex1, a guanine nucleotide exchange factor, positively regulates Rac1-mediated oncogenic signaling. P-Rex1 is overexpressed in a subset of human breast cancers however, little is known of its function in vivo. Here we show P-Rex1 regulates Rac1 activation in vivo in the mammary gland. Increased P-Rex1 expression enhances mammary epithelial cell proliferation and is causally associated with tumor initiation. In murine models, P-Rex1 cooperates with the neu oncogene to increase mammary tumor incidence and metastasis but not primary tumor growth. Our studies suggest that inhibiting the P-Rex1–Rac1 signaling axis may be an adjunct therapy for treating invasive cancers which exhibit increased P-Rex1 expression.
Publisher: Wiley
Date: 05-03-2009
Publisher: American Association for Cancer Research (AACR)
Date: 15-01-2009
DOI: 10.1158/1078-0432.CCR-08-1022
Abstract: Purpose: Multiple myeloma is an incurable disease with heterogeneous clinical behavior. Bortezomib has offered some patients with relapsed and refractory disease an opportunity for prolonged survival. However, there remains a paucity of data in patients treated with bortezomib that accurately delineates and identifies such patients. This information is crucial to guide management. Experimental Design: In this study, we aimed to identify the patients most likely to respond to bortezomib salvage therapy. We analyzed the baseline clinical variables and profiled the baseline expression of a broad range of immunohistochemical markers of cell cycle activity, apoptosis, and angiogenesis in a large cohort of multiply relapsed myeloma patients recruited to one of two prospective multicentre trials assessing the efficacy of bortezomib salvage therapy. Results: Using the European Group for Bone Marrow Transplantation criteria, response (complete or partial) to bortezomib salvage therapy was associated with a previous history of complete response to alternative antimyeloma treatment. Patients who expressed cyclin D1 were more likely to achieve a response. In contrast, patients who expressed p16INK4A, cytoplasmic p53, and the highest intensity of Bcl-2 staining had a poor response. Patients who achieved a response to bortezomib and those patients who expressed cyclin D1 at baseline showed a significant survival advantage. Patients who expressed FGFR3, a poor prognostic marker, responded equally well and had similar outcomes with bortezomib compared with FGFR3-negative patients. Conclusions: Baseline clinical variables and selective immunohistochemical markers expressed by patients may be used effectively to identify patients that are most likely to achieve a meaningful clinical response to bortezomib salvage therapy.
Publisher: Springer Science and Business Media LLC
Date: 23-08-2015
DOI: 10.1007/S00401-015-1468-2
Abstract: Several erse proteins are linked genetically athologically to neurodegeneration in amyotrophic lateral sclerosis (ALS) including SOD1, TDP-43 and FUS. Using a variety of cellular and biochemical techniques, we demonstrate that ALS-associated mutant TDP-43, FUS and SOD1 inhibit protein transport between the endoplasmic reticulum (ER) and Golgi apparatus in neuronal cells. ER-Golgi transport was also inhibited in embryonic cortical and motor neurons obtained from a widely used animal model (SOD1(G93A) mice), validating this mechanism as an early event in disease. Each protein inhibited transport by distinct mechanisms, but each process was dependent on Rab1. Mutant TDP-43 and mutant FUS both inhibited the incorporation of secretory protein cargo into COPII vesicles as they bud from the ER, and inhibited transport from ER to the ER-Golgi intermediate (ERGIC) compartment. TDP-43 was detected on the cytoplasmic face of the ER membrane, whereas FUS was present within the ER, suggesting that transport is inhibited from the cytoplasm by mutant TDP-43, and from the ER by mutant FUS. In contrast, mutant SOD1 destabilised microtubules and inhibited transport from the ERGIC compartment to Golgi, but not from ER to ERGIC. Rab1 performs multiple roles in ER-Golgi transport, and over-expression of Rab1 restored ER-Golgi transport, and prevented ER stress, mSOD1 inclusion formation and induction of apoptosis, in cells expressing mutant TDP-43, FUS or SOD1. Rab1 also co-localised extensively with mutant TDP-43, FUS and SOD1 in neuronal cells, and Rab1 formed inclusions in motor neurons of spinal cords from sporadic ALS patients, which were positive for ubiquitinated TDP-43, implying that Rab1 is misfolded and dysfunctional in sporadic disease. These results demonstrate that ALS-mutant forms of TDP-43, FUS, and SOD1 all perturb protein transport in the early secretory pathway, between ER and Golgi compartments. These data also imply that restoring Rab1-mediated ER-Golgi transport is a novel therapeutic target in ALS.
Publisher: BMJ
Date: 11-2000
Abstract: As clinical diagnosis of Alzheimer's disease is only 80%-90% accurate, there is a need to identify biochemical markers of Alzheimer's disease. Previous studies have shown an abnormality in the glycosylation of acetylcholinesterase (AChE) in the CSF collected postmortem from patients with Alzheimer's disease. This abnormality was very specific for Alzheimer's disease, as it was not detected in other illnesses causing dementia. We report here that the glycosylation of AChE is also altered in lumbar CSF collected antemortem. The altered glycosylation was due to increased concentrations of a minor AChE isoform that does not bind to concanavalin A (Con A). Glycosylation of AChE may eventually be of diagnostic value, especially when used in combination with other CSF markers.
Publisher: Wiley
Date: 08-10-2015
DOI: 10.1002/AJH.24179
Publisher: Proceedings of the National Academy of Sciences
Date: 02-12-2010
Abstract: Inositol polyphosphate 4-phosphatase-II (INPP4B) is a regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway and is implicated as a tumor suppressor in epithelial carcinomas. INPP4B loss of heterozygosity (LOH) is detected in some human breast cancers however, the expression of INPP4B protein in breast cancer subtypes and the normal breast is unknown. We report here that INPP4B is expressed in nonproliferative estrogen receptor (ER)-positive cells in the normal breast, and in ER-positive, but not negative, breast cancer cell lines. INPP4B knockdown in ER-positive breast cancer cells increased Akt activation, cell proliferation, and xenograft tumor growth. Conversely, reconstitution of INPP4B expression in ER-negative, INPP4B-null human breast cancer cells reduced Akt activation and anchorage-independent growth. INPP4B protein expression was frequently lost in primary human breast carcinomas, associated with high clinical grade and tumor size and loss of hormone receptors and was lost most commonly in aggressive basal-like breast carcinomas. INPP4B protein loss was also frequently observed in phosphatase and tensin homolog (PTEN)-null tumors. These studies provide evidence that INPP4B functions as a tumor suppressor by negatively regulating normal and malignant mammary epithelial cell proliferation through regulation of the PI3K/Akt signaling pathway, and that loss of INPP4B protein is a marker of aggressive basal-like breast carcinomas.
Publisher: Elsevier BV
Date: 2018
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.NEUROBIOLAGING.2005.03.014
Abstract: Phosphatidylethanolamine binding protein (PEBP) is a multifunctional protein, with proposed roles as the precursor protein of hippoc al cholinergic neurostimulating peptide (HCNP), and as the Raf kinase inhibitor protein (RKIP). Previous studies have demonstrated a decrease in PEBP mRNA in CA1 region of AD hippoc us. The current study demonstrates that PEBP is decreased in the hippoc us of 11 month Tg2576 mice, in the absence of change in mRNA levels compared to non-transgenic littermates. The level of PEBP in transgenic mouse hippoc us significantly decreases at 11 months (a time point when Abeta begins accumulating) and 15 months (when Abeta plaques have formed). There was a significant correlation between decreased PEBP expression and accumulation of Abeta. Immunohistochemical studies on Tg2576 and AD brain sections demonstrate that PEBP immunoreactivities are present at the periphery of dense multicore Abeta plaques, and in selective astrocytes, primarily surrounding plaques. These findings suggest that PEBP expression may be influenced by accumulation of Abeta. Down-regulation of PEBP may result in lower levels of HCNP or altered coordination of signal transduction pathways that may contribute to neuronal dysfunction and pathogenesis in AD.
Publisher: Cold Spring Harbor Laboratory
Date: 29-04-2022
DOI: 10.1101/2022.04.28.489869
Abstract: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved. To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). Finally, we utilised the SOD1 G37R mouse model of ALS and a novel CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo . We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Moreover, a molecular correlation between ferroptosis and neurotoxic astrocytes evident in ALS-affected spinal cord is recapitulated in the SOD1 G37R mouse model where treatment with the novel, CNS-permeant ferroptosis inhibitor, Cu II (atsm), ameliorated these markers and was neuroprotective. By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.
Publisher: Wiley
Date: 29-04-2009
Publisher: Springer Science and Business Media LLC
Date: 19-06-2011
DOI: 10.1038/NG.859
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S0014-4886(03)00004-9
Abstract: Multiple system atrophy (MSA) belongs to synucleinopathies and is characterized pathologically by oligodendroglial inclusions (GCIs) composed of 20- to 30-nm tubular filaments. alpha-Synuclein fibrils formed in vitro, however, range between 10 and 12 nm in diameter. To understand the relationship between alpha-synuclein and GCI filaments, we conducted structural analyses of GCIs in fixed brain sections and isolated from fresh-frozen MSA brains. In fixed brain sections, GCIs were composed of amorphous material-coated filaments up to 30 nm in size. The filaments were often organized in parallel bundles extending into oligodendroglial processes. In freshly isolated GCIs, progressive buffer washes removed amorphous material and revealed that GCI filaments consisted of 10-nm-sized central core fibrils that were strongly alpha-synuclein immunoreactive. Image analysis revealed that each core fibril was made of two subfibrils, and each subfibril was made of a string of 3- to 6-nm-sized particles probably alpha-synuclein oligomers. Immunogold labeling demonstrated that epitopes encompassing entire alpha-synuclein molecule were represented in the core fibrils, with the N-terminal 11-26 and C-terminal 108-131 amino acid residues most accessible to antibodies, probably exposed on the surface of the fibril. Our study indicates that GCI filaments are multilayered in structure, with alpha-synuclein oligomers forming the central core fibrils of the filaments.
Publisher: Cambridge University Press (CUP)
Date: 29-06-2017
DOI: 10.1017/S1041610217001193
Abstract: Fronto-temporal dementia (FTD) associated with Fused in Sarcoma (FUS) protein accumulation is an uncommon cause of FTD with a distinct syndrome of young age onset behavioral variant FTD, without a family history of FTD and caudate atrophy. We present a sporadic case of a 61-year-old patient with mixed features of both behavioral variant FTD with later semantic language dissolution associated with pathologically proven FUS. He was older than usual for FUS pathology, his course was rapidly progressive, and he had atypical language features. This case broadens the clinical spectrum caused by FUS-protein-related FTD.
Publisher: Wiley
Date: 31-05-2002
DOI: 10.1002/ANA.10224
Abstract: Through the Australian National Creutzfeldt-Jakob Disease Registry, 6 pathologically confirmed sporadic cases were recognized over a 13-year period in persons who had been long-term residents of a moderate-sized rural city, whereas the expected number was 0.923. An extensive investigation could not find any point-source or case-to-case transmission links. This occurrence is highly statistically significant (p = 0.0027) when viewed in isolation and remains significant (p < 0.02) when only the cases that arose after the cluster was recognized were taken into account. However, a more conservative statistical analysis suggests that such a grouping could have arisen by chance in at least one population group of this size when the whole country is taken into consideration.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2017
Publisher: Springer Science and Business Media LLC
Date: 29-08-2013
Publisher: Wiley
Date: 08-03-2013
DOI: 10.1111/BPA.12041
Publisher: American Association for Cancer Research (AACR)
Date: 09-2017
DOI: 10.1158/1535-7163.MCT-16-0624
Abstract: Currently available treatment options are unlikely to be curative for the majority of multiple myeloma patients, emphasizing a continuing role for the introduction of investigational agents that can overcome drug resistance. The canonical Wnt/β-catenin signaling pathway, essential for self-renewal, growth, and survival, has been found to be dysregulated in multiple myeloma, particularly in advanced stages of disease. This provides the rationale for evaluating the novel β-catenin inhibitor BC2059 as monotherapy and in combination with proteasome inhibitors in vitro and in vivo. Here, we show nuclear localization of β-catenin in human myeloma cell lines (HMCL), consistent with activation of the canonical Wnt pathway. BC2059 attenuates β-catenin levels, in both the cytoplasm and the nucleus, reducing the transcriptional activity of the TCF4/LEF complex and the expression of its target gene axin 2. Treatment of HMCL with BC2059 inhibits proliferation and induces apoptosis in a dose-dependent manner. This is also observed in HMCL–stromal cell cocultures, mitigating the protective effect afforded by the stroma. Similarly, BC2059 induces apoptosis in primary multiple myeloma s les in vitro, causing minimal apoptosis on healthy peripheral blood mononuclear cells. Furthermore, it synergizes with the proteasome inhibitor bortezomib both in HMCL and primary multiple myeloma s les. Finally, in xenograft models of human myelomatosis, BC2059 delays tumor growth and prolongs survival with minor on-target side effects. Collectively, these results demonstrate the efficacy of targeting the Wnt/β-catenin pathway with BC2059 both in vitro and in vivo, at clinically achievable doses. These findings support further clinical evaluation of BC2059 for the treatment of multiple myeloma. Mol Cancer Ther 16(9) 1765–78. ©2017 AACR.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2019
DOI: 10.1007/S11695-018-3479-2
Abstract: Non-alcoholic fatty liver disease (NAFLD), driven by the obesity epidemic, has become the most common form of liver disease. Despite this, there is controversy regarding the prevalence and severity of NAFLD in obesity. Obesity-related factors, such as increasing adiposity, metabolic disease and inflammation, may influence prevalence. We therefore prospectively measured NAFLD prevalence in obesity and studied factors associated with NAFLD. We recruited consecutive bariatric patients. Intraoperative liver biopsies were taken. The liver, adipose tissue and serum were collected to measure inflammation. Adipocyte cell size was measured. NAFLD severity was correlated to body mass index (BMI), metabolic health and adipose characteristics. There were 216 participants BMI 45.9 ± 8.9 kg/m NAFLD remains endemic in obesity however, NASH/steatofibrosis are less common than previously reported. Worsening obesity and metabolic disease increase odds of NAFLD independently, with substantially compounded effect with both. These observations may help with risk stratification in obese populations. We were unable to delineate clear associations between adipose inflammation and NASH/steatofibrosis in this obese population. Australian Clinical Trials Registry ( ACTRN12615000875505 ).
Publisher: Springer Science and Business Media LLC
Date: 03-04-2012
Abstract: Microvascular sequestration of Plasmodium falciparum underlies cerebral malaria. Despite suggestive ex vivo evidence, this phenomenon has not been convincingly demonstrated in coma complicating Plasmodium vivax malaria. Severely-ill Papua New Guinean children with mixed P. falciparum/P. vivax infections are more likely to develop cerebral malaria and die than those with P. falciparum alone, possibly reflecting P. vivax sequestration. Nested PCR was performed on post mortem brain tissue from three such children dying from cerebral malaria due to mixed-species infections. No P. vivax DNA was detected. These findings do not support the hypothesis that P. vivax sequestration occurs in human brain.
Publisher: Wiley
Date: 30-03-2016
DOI: 10.1111/NAN.12285
Publisher: Wiley
Date: 15-10-2015
DOI: 10.1111/NAN.12286
Abstract: Cholesterol plays an essential role in membrane structure and function, being especially important in the brain. Alteration of brain cholesterol synthesis and metabolism has been demonstrated in several Huntington's disease (HD) mouse and cell models however, less is known about these alterations in human tissue. This study aimed to identify alterations to cholesterol synthetic and metabolic pathways in human HD brain tissue. A broad range of cholesterol synthetic precursors, metabolites and oxidation products were measured by gas chromatography-tandem mass spectrometry in five regions of human post mortem HD brain and compared with age- and sex-matched control tissues. The level of enzymes that regulate cholesterol homeostasis, cholesterol 24-hydroxylase and delta(24)-sterol reductase were investigated by Western blotting and qPCR in putamen. The most significant changes were localized to the putamen, where a 60% decrease in 24(S)-hydroxycholesterol, 30% increase in cholesterol and 100-200% increase in synthetic precursors (lathosterol, zymosterol and desmosterol) was detected. The enzymes cholesterol 24-hydroxylase and delta(24)-sterol reductase were also significantly decreased in HD putamen as compared with control tissues. Free radical-generated cholesterol oxidation products 7-keto cholesterol and 7β-hydroxycholesterol were also increased by 50-70% in HD putamen. Human HD brain has significantly decreased cholesterol metabolism and disrupted cholesterol homeostasis. Our data also indicate that lipid oxidative stress accompanies HD pathology.
Publisher: Elsevier BV
Date: 08-2004
Publisher: Oxford University Press (OUP)
Date: 03-2012
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.JSBMB.2017.07.029
Abstract: Androgen deprivation therapy (ADT) decreases muscle mass and function but no human studies have investigated the underlying genetic or cellular effects. We tested the hypothesis that ADT will lead to changes in skeletal muscle gene expression, which may explain the adverse muscle phenotype seen clinically. We conducted a prospective cohort study of 9 men with localised prostate cancer who underwent a vastus lateralis biopsy before and after 4 weeks of ADT. Next-generation RNA sequencing was performed and genes differentially expressed following ADT underwent gene ontology mining using Ingenuity Pathway Analysis. Differential expression of genes of interest was confirmed by quantitative PCR (Q-PCR) on gastrocnemius muscle of orchidectomised mice and sham controls (n=11/group). We found that in men, circulating total testosterone decreased from 16.5±4.3nmol/L at baseline to 0.4±0.15nmol/L post-ADT (p<0.001). RNA sequencing identified 19 differentially expressed genes post-ADT (all p<0.05 after adjusting for multiple testing). Gene ontology mining identified 8 genes to be of particular interest due to known roles in androgen-mediated signalling ABCG1, ACTC1, ANKRD1, DMPK, THY1, DCLK1, CST3 were upregulated and SLC38A3 was downregulated post-ADT. Q-PCR in mouse gastrocnemius muscle confirmed that only one gene, Actc1 was concordantly upregulated (p<0.01) in orchidectomised mice compared with controls. In conclusion, given that ACTC1 upregulation is associated with improved muscle function in certain myopathies, we hypothesise that upregulation of ACTC1 may represent a compensatory response to ADT-induced muscle loss. Further studies will be required to evaluate the role and function of ACTC1.
Publisher: Elsevier BV
Date: 02-2004
Publisher: Elsevier BV
Date: 12-2014
Publisher: Oxford University Press (OUP)
Date: 12-2015
DOI: 10.2146/AJHP150171
Abstract: The case of a patient who experienced a severe adverse reaction requiring emergency treatment after a single dose of fenofibrate is described. A 58-year-old woman with type 1 diabetes was hospitalized for treatment of an extensive blistering rash on the buttocks and trunk accompanied by fever, hypotension, tachycardia, neutrophilia, impaired renal function, and liver enzyme abnormalities. She reported that two days previously she had developed fever and vomiting four hours after taking her first dose of fenofibrate (145 mg). The patient required vasopressor support and was initially treated with broad-spectrum antibiotics for 3 days and a course of immune globulin. On hospital day 4, histopathology returned results consistent with acute generalized exanthematous pustulosis (AGEP), and the patient was subsequently treated with topical steroids. Gradual resolution of AGEP was noted at the time of her discharge from the hospital on day 7 and at one-week follow-up. Analysis of the case using the adverse drug reaction probability scale of Naranjo et al. yielded a score of 5, indicating a probable association between fenofibrate use and AGEP development. AGEP is a predominantly drug-induced condition but is not typically associated with fenofibrate use. Cutaneous eruptions in AGEP are often accompanied by systemic symptoms (e.g., fever, leukocytosis), and the disorder can also be associated with impaired creatinine clearance and elevated aminotransaminase levels. A woman with type 1 diabetes developed AGEP after taking a single dose of fenofibrate. Her cutaneous symptoms began to resolve within days of discontinuation of fenofibrate use.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.JOCN.2018.10.084
Abstract: A previously well man presented with several months' history of neurological symptoms including diplopia and balance difficulties. Examination revealed fluctuating neurological deficits, fatigable weakness and slowed saccades. Extensive testing revealed mildly elevated cerebrospinal fluid protein, strongly positive single fiber electromyography and a dorsal pontine lesion at the floor of the 4th ventricle. An autoimmune process was felt to best account for the myasthenic presentation while the differential diagnoses for the brainstem lesion included glioma. Aggressive immunotherapy failed to halt clinical deterioration over months he developed generalized weakness, aspiration pneumonia and died. Post-mortem analysis revealed glioneuronal tumor infiltration throughout the brainstem, cerebellum and along the meningeal surface. This is an unusual case of an infiltrative brainstem lesion, with the presentation suggesting a primary diagnosis of myasthenia gravis. The progressive nature of the illness, despite aggressive immune therapy, together with slow saccades, underscored a more sinister process. Cerebral imaging should be performed in patients with fluctuating neurological symptoms, progressive deterioration, and ocular, bulbar, respiratory, or pyramidal pattern deficits, and differentials for contrast-enhancing brain lesions should include primary brain tumors. In such cases, biopsy must proceed if the disease is of relatively recent onset, to facilitate diagnosis and maximize treatment opportunities.
Publisher: Wiley
Date: 28-11-2014
DOI: 10.1111/AJD.12121
Abstract: Although there has been improvement in clinical diagnosis of pigmented superficial spreading melanomas (SSM), less common melanoma subtypes have different clinical features and may be more difficult to diagnose. The objective was to assess diagnostic accuracy for different melanoma subtypes. A retrospective review was made of a random selection of SSM, nodular melanomas (NM), desmoplastic melanomas (DM) and acral lentiginous melanomas (ALM) biopsied between February 2001 and May 2012 and referred to the Victorian Melanoma Service. Clinical differential diagnoses listed on pre-operative biopsy pathology request forms were recorded. Sensitivity for the diagnosis of melanoma was used as a marker of diagnostic accuracy. In total 111 SSM, 121 NM, 43 DM and 30 ALM were biopsied by 222 clinicians. Whereas diagnostic sensitivity for SSM and ALM were similar (77%, 95% CI 69-85% and 73%, 95% CI 58-89%, respectively) diagnostic sensitivity was lower for NM (41%, 95% CI 33-50%) and DM (21%, 95% CI 9-33%). Both NM and DM were diagnosed at greater tumour thickness (median 3.0 mm and 4.0 mm) than SSM and ALM (both median 1.0 mm). Amelanosis was associated with lower diagnostic sensitivity for SSM (0 vs 82%, P < 0.01), NM (19 vs 51%, P < 0.01) andDM (10 vs 32%, P = 0.07). Dermatologists were more accurate than non-dermatologists for NM (diagnostic sensitivity 57 vs 32%, P < 0.01) and ALM (diagnostic sensitivity 94 vs 43%, P = 0.02). Misdiagnosis of melanoma varies according to subtype and is particularly problematic for NM, DM and hypopigmented melanomas. Greater awareness of the different criteria required to diagnose these melanomas is needed.
Publisher: Mary Ann Liebert Inc
Date: 03-2010
Abstract: Little is known about the molecular events following severe traumatic brain injury (TBI) in humans and to date there are no efficient therapies for the treatment of patients. In this study, the first of its kind in human tissue, a total of 21 post mortem trauma brain s les were analyzed. The inflammatory response within the brain tissue was explored by measuring the expression of various inflammatory cytokines at the mRNA and protein levels. These mediators were interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF). This study shows for the first time in human brain tissue that 1) pro-inflammatory mediator protein levels are significantly increased in situ following acute brain injury while anti-inflammatory cytokines protein levels remain unchanged 2) the cerebral inflammatory response begins within minutes of acute TBI, much earlier than previously thought 3) IL-6, IL-8, TNF-alpha, and IL-1beta mRNA levels are significantly increased following injury 4) the rise in cytokine protein level coincides with increased levels of their mRNAs suggesting that traumatic injury elicits an immediate cerebral inflammatory response. Altogether these data confirm and extend previous observations on the release of cytokines in the cerebrospinal fluid of severe TBI patients. Finally, this study highlights the need to characterize the cell source of cytokines and elucidate their mode of action.
Publisher: Wiley
Date: 09-2001
DOI: 10.1046/J.1440-1622.2001.02185.X
Abstract: Pancreaticoduodenectomy (PD) is considered to be the optimal treatment for ullary adenocarcinomas. Local resection (LR) is a less invasive and potentially equally effective alternative for cancers with favourable prognostic features. Identification of these prognostic parameters may allow selection of patients suitable for LR. Twenty-five patients were treated for a primary Vater's ulla adenocarcinoma at the Alfred Hospital, Melbourne, Australia, between January 1989 and January 2000. Risk factors for cancer recurrence were evaluated and the specific role of LR was defined. Fourteen patients had PD, five had LR and six had bypass procedures (five biliary stents one operative bypass). Presenting symptoms included jaundice (64%), abdominal pain (54%) and weight loss (32%). Adenocarcinomas that were resected had a median diameter of 2.5 cm, and were limited to the ulla in 26% (T1), invaded the duodenal wall in 42% (T2) and infiltrated 2 cm or less into the pancreas in 32% (T1) of cases. Locally resected cancers were confined to the ulla or invaded the duodenum and recurred in one patient following excision. Six recurrences occurred in total, influenced significantly by T staging (P = 0.009). Patient age, preoperative symptoms, laboratory tests, tumour size, differentiation, ulceration, lymphovascular spread and perineural invasion had no effect on recurrence. Patients undergoing LR had lower morbidity and mortality, reduced blood transfusion requirements and shorter hospital stay than those treated by PD. T staging predicts the risk of tumour recurrence and can be determined using endoscopic ultrasound. Local resection is a suitable alternative to pancreaticoduodenal resection in patients with T1 and T2 adenocarcinomas with a maximum diameter of 3 cm or less.
Publisher: Springer Science and Business Media LLC
Date: 2014
DOI: 10.1186/ALZRT240
Publisher: Wiley
Date: 30-03-2020
Publisher: Springer Science and Business Media LLC
Date: 15-08-2014
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.JAAD.2014.04.068
Abstract: To calculate melanoma rate of growth (ROG), previous studies have relied on subjective patient recall to estimate time delay to diagnosis. To objectively calculate ROG by measuring the rate of increase in melanoma thickness between 2 sequential biopsy specimens over time. This was a retrospective review of 51 melanomas in which pathologic misdiagnosis of a partial biopsy specimen caused a delay before referral and excisional biopsy between January 1998 and January 2013. ROG was calculated as rate of increase in tumor thickness between biopsy specimens. The median delay between the 2 biopsy specimens was 27 months (range, 3-89 months). Biopsy specimens of melanomas that were obtained initially in their in situ phase were thinner at excision compared to those that were first obtained as invasive tumors (median, 0.7 vs. 3.2 mm P<.01) and had a lower ROG (median, 0.04 vs. 0.11 mm/month P=.05). Faster growth was associated with increased tumor thickness, higher mitotic rate, symptoms, elevation, and amelanosis. Partial biopsy specimens may not be representative of deepest tumor thickness. We have demonstrated an objective measure of melanoma growth rate using sequential biopsy specimens. The correlation between faster growth and aggressive tumor features supports what others have found and validates the historical measure of growth rate as a reliable clinical marker.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2013
DOI: 10.1158/1078-0432.CCR-13-0398
Abstract: Purpose: The mutation load in melanoma is generally high compared with other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinicopathologic features. Experimental Design: DNA was extracted from 34 fresh-frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was conducted and mutation rates were correlated with age, sex, tumor site, and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation, and BRAF/NRAS mutational status were investigated. Results: The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared with 3.8 per Mb in non-SSD skin (P = 0.001). BRAF/NRAS wild-type (WT) tumors had a higher average mutation rate compared with BRAF/NRAS–mutant tumors (27 vs. 5.6 mutations per Mb P = 0.0001). Tandem CC& TT/GG& AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (P = 0.0008) and in BRAF/NRAS WT tumors (P = 0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1, KIT, and NOTCH1, were spread over various signaling pathways. Conclusion: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF- and NRAS-mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients. Clin Cancer Res 19(17) 4589–98. ©2013 AACR.
Publisher: American Physiological Society
Date: 10-2009
Abstract: The influence of circulating urotensin II (UII) on liver disease and portal hypertension is unknown. We aimed to evaluate whether UII executes a pathogenetic role in the development of hepatic fibrosis and portal hypertension. UII was administered by continuous infusion over 4 wk in 20 healthy rats ided into three treatment groups, controls (saline, n = 7), low dose (UII, 1 nmol·kg −1 ·h −1 , n = 8), and high dose (UII, 3 nmol·kg −1 ·h −1 , n = 5). Hemodynamic parameters and morphometric quantification of fibrosis were assessed, and profibrotic cytokines and fibrosis markers were assayed in hepatic tissue. UII induced a significant dose-dependent increase in portal venous pressure (5.8 ± 0.4, 6.4 ± 0.3, and 7.6 ± 0.7, respectively, P = 0.03). High-dose UII infusion was associated with an increase in hepatic transcript for transforming growth factor-β ( P 0.05) and platelet-derived growth factor-β ( P = 0.06). Liver tissue hydroxyproline was elevated in the high-dose group ( P 0.05). No systemic hemodynamic alterations were noted. We concluded that UII infusion elevates portal pressure and induces hepatic fibrosis in normal rats. This response may be mediated via induction of fibrogenic cytokines. These findings have pathophysiological implications in human liver disease where increased plasma UII levels have been observed.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.JINORGBIO.2016.02.029
Abstract: Gallium-68 is a positron-emitting isotope that can be used in positron-emission tomography imaging agents. Alzheimer's disease is associated with the formation of plaques in the brain primarily comprised of aggregates of a 42 amino acid protein called amyloid-β. With the goal of synthesising charge neutral, low molecular weight, lipophilic gallium complexes with the potential to cross the blood-brain barrier and bind to Aβ plaques we have used an ancillary tetradentate N
Publisher: Springer Science and Business Media LLC
Date: 27-05-2012
DOI: 10.1038/NG.2293
Publisher: Oxford University Press (OUP)
Date: 10-11-2010
DOI: 10.1093/BRAIN/AWP267
Abstract: Amyotrophic lateral sclerosis is a rapidly progressing fatal neurodegenerative disease characterized by the presence of protein inclusions within affected motor neurons. Endoplasmic reticulum stress leading to apoptosis was recently recognized to be an important process in the pathogenesis of sporadic human amyotrophic lateral sclerosis as well as in transgenic models of mutant superoxide dismutase 1-linked familial amyotrophic lateral sclerosis. Endoplasmic reticulum stress occurs early in disease, indicating a critical role in pathogenesis, and involves upregulation of an important endoplasmic reticulum chaperone, protein disulphide isomerase. We aimed to investigate the involvement of protein disulphide isomerase in endoplasmic reticulum stress induction, protein aggregation, inclusion formation and toxicity in amyotrophic lateral sclerosis. Motor neuron-like NSC-34 cell lines were transfected with superoxide dismutase 1 and protein disulphide isomerase encoding vectors and small interfering RNA, and examined by immunocytochemistry and immunoblotting. Expression of mutant superoxide dismutase 1 induced endoplasmic reticulum stress, predominantly in cells bearing mutant superoxide dismutase 1 inclusions but also in a proportion of cells expressing mutant superoxide dismutase 1 without visible inclusions. Over-expression of protein disulphide isomerase decreased mutant superoxide dismutase 1 aggregation, inclusion formation, endoplasmic reticulum stress induction and toxicity, whereas small interfering RNA targeting protein disulphide isomerase increased mutant superoxide dismutase 1 inclusion formation, indicating a protective role for protein disulphide isomerase against superoxide dismutase 1 misfolding. Aberrant modification of protein disulphide isomerase by S-nitrosylation of active site cysteine residues has previously been shown as an important process in neurodegeneration in Parkinson's and Alzheimer's disease brain tissue, but has not been described in amyotrophic lateral sclerosis. Using a biotin switch assay, we detected increased levels of S-nitrosylated protein disulphide isomerase in transgenic mutant superoxide dismutase 1 mouse and human sporadic amyotrophic lateral sclerosis spinal cord tissues. Hence, despite upregulation, protein disulphide isomerase is also functionally inactivated in amyotrophic lateral sclerosis, which may prevent its normal protective function and contribute to disease. We also found that a small molecule mimic of the protein disulphide isomerase active site, (+/-)-trans-1,2-bis(mercaptoacetamido)cyclohexane, protected against mutant superoxide dismutase 1 inclusion formation. These studies reveal that endoplasmic reticulum stress is important in the formation of mutant superoxide dismutase 1 inclusions, and protein disulphide isomerase has an important function in ameliorating mutant superoxide dismutase 1 aggregation and toxicity. Functional inhibition of protein disulphide isomerase by S-nitrosylation may contribute to pathophysiology in both mutant superoxide dismutase 1-linked disease and sporadic amyotrophic lateral sclerosis. Protein disulphide isomerase is therefore a novel potential therapeutic target in amyotrophic lateral sclerosis and (+/-)-trans-1,2-bis(mercaptoacetamido)cyclohexane and other molecular mimics of protein disulphide isomerase could be of benefit in amyotrophic lateral sclerosis and other neurodegenerative diseases related to protein misfolding.
Publisher: Wiley
Date: 09-2013
DOI: 10.1086/674339
Abstract: Pulmonary arterial remodeling has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD), but it is not known whether lobar heterogeneity of remodeling occurs. Furthermore, the relationship between pulmonary hypertension (PH) and pulmonary arterial remodeling in COPD has not been established. Muscular pulmonary arterial remodeling in arteries 0.10–0.25 mm in diameter was assessed in COPD‐explanted lungs and autopsy controls. Remodeling was quantified as the percentage wall thickness to vessel diameter (%WT) using digital image analysis. Repeat measures mixed‐effects remodeling for %WT was performed according to lobar origin (upper and lower), muscular pulmonary arterial size (small, medium, and large), and echocardiography‐based pulmonary arterial pressure (no PH, mild PH, and moderate‐to‐severe PH). Lobar perfusion and emphysema indices were determined from ventilation‐perfusion and computed tomography scans, respectively. Overall, %WT was greater in 42 subjects with COPD than in 5 control subjects ( P 0.0001). Within the COPD group, %WT was greater in the upper lobes ( P 0.0001) and in the small muscular pulmonary arteries ( P 0.0001). Lobar differences were most pronounced in medium and large arteries. Lobar emphysema index was not associated with arterial remodeling. However, there was a significant positive relationship between the lobar perfusion index and pulmonary arterial remodeling ( P = 0.024). The presence of PH on echocardiography showed only a trend to a small effect on lower lobe remodeling. The pattern of pulmonary arterial remodeling in COPD is complicated and lobe dependent. Differences in regional blood flow partially account for the lobar heterogeneity of pulmonary arterial remodeling in COPD.
Publisher: American Society for Clinical Investigation
Date: 28-10-2021
Publisher: SAGE Publications
Date: 08-02-2017
Publisher: Oxford University Press (OUP)
Date: 14-03-2014
DOI: 10.1093/HMG/DDU119
Abstract: All cases of Huntington's disease (HD) are caused by mutant huntingtin protein (mhtt), yet the molecular mechanisms that link mhtt to disease symptoms are not fully elucidated. Given glycogen synthase kinase-3 (GSK3) is implicated in several neurodegenerative diseases as a molecular mediator of neuronal decline and widely touted as a therapeutic target, we investigated GSK3 in cells expressing mhtt, brains of R6/1 HD mice and post-mortem human brain s les. Consistency in data across the two models and the human brain s les indicate decreased GSK3 signalling contributes to neuronal dysfunction in HD. Inhibitory phosphorylation of GSK3 (pGSK3) was elevated in mhtt cells and this appeared related to an overall energy metabolism deficit as the mhtt cells had less ATP and inhibiting ATP production in control cells expressing non-pathogenic htt with paraquat also increased pGSK3. pGSK3 was increased and ATP levels decreased in the frontal cortex and striatum of R6/1 mice and levels of cortical pGSK3 inversely correlated with cognitive function of the mice. Consistent with decreased GSK3 activity in the R6/1 mouse brain, β-catenin levels were increased and phosphorylation of collapsin response mediator protein-2 (CRMP2) decreased in the frontal cortex where inhibitory phosphorylation of GSK3 was the greatest. pGSK3 was predominantly undetectable in HD and healthy control human brain s les, but levels of total GSK3 were decreased in the HD-affected frontal cortex and this correlated with decreased pCRMP2. Thus, disruptions to cortical GSK3 signalling, possibly due to localized energy metabolism deficits, appear to contribute to the cognitive symptoms of HD.
Publisher: American Chemical Society (ACS)
Date: 03-05-2017
DOI: 10.1021/ACSCHEMNEURO.7B00014
Abstract: The antioxidant activity of selenium, which is mainly conferred by its incorporation into dedicated selenoproteins, has been suggested as a possible neuroprotective approach for mitigating neuronal loss in Alzheimer's disease. However, there is inconsistent information with respect to selenium levels in the Alzheimer's disease brain. We examined the concentration and cellular compartmentalization of selenium in the temporal cortex of Alzheimer's disease and control brain tissue. We found that Alzheimer's disease was associated with decreased selenium concentration in both soluble (i.e., cytosolic) and insoluble (i.e., plaques and tangles) fractions of brain homogenates. The presence of the APOE ε4 allele correlated with lower total selenium levels in the temporal cortex and a higher concentration of soluble selenium. Additionally, we found that age significantly contributed to lower selenium concentrations in the peripheral membrane-bound and vesicular fractions. Our findings suggest a relevant interaction between APOE ε4 and selenium delivery into brain, and show changes in cellular selenium distribution in the Alzheimer's disease brain.
Publisher: Springer Science and Business Media LLC
Date: 07-09-2016
DOI: 10.1007/S10549-016-3971-0
Abstract: Aberrant DNA methylation occurs frequently in breast carcinogenesis. Tools for translational epigenetic studies of breast cancer involving formalin-fixed paraffin-embedded (FFPE) human tissues have now been developed. Few studies have measured genome-wide methylation in DNA derived from paraffin-embedded tumour tissues and compared the DNA methylation in corresponding adjacent non-tumour ductal epithelium (ADJ Twenty-one archival breast tumour tissues with paired ADJ The 1000 most differentially methylated probes between tumour and ADJ Large-scale studies of genome-wide DNA methylation using FFPE breast cancer specimens offer the opportunity to further refine the pathological classification of tumours, to include subtypes that are underrepresented in the TCGA data and provide the capacity to further explore intra-tumoural heterogeneity.
Publisher: Society for Neuroscience
Date: 07-2018
DOI: 10.1523/ENEURO.0234-18.2018
Abstract: The neurodegenerative Huntington’s disease (HD) is caused by a polyglutamine (polyQ) lification in the huntingtin protein (HTT). Currently there is no effective therapy available for HD however, several efforts are directed to develop and optimize HTT-lowering methods to improve HD phenotypes. To validate these approaches, there is an immediate need for reliable, sensitive, and easily accessible methods to quantify HTT expression. Using the AlphaLISA platform, we developed two novel sensitive and robust assays for quantification of HTT in biological s les using commercially available antibodies. The first, a polyQ-independent assay, measures the total pool of HTT, while the second, a polyQ-dependent assay, preferentially detects the mutant form of HTT. Using purified HTT protein standards and brain homogenates from an HD mouse model, we determine a lower limit of quantification of 1 and 3 p m and optimal reproducibility with CV values lower than 7% for intra- and 20% for interassay. In addition, we used the assays to quantify HTT in neural stem cells generated from patient-derived induced pluripotent stem cells in vitro and in human brain tissue lysates. Finally, we could detect changes in HTT levels in a mouse model where mutant HTT was conditionally deleted in neural tissue, verifying the potential to monitor the outcome of HTT-lowering strategies. This analytical platform is ideal for high-throughput screens and thus has an added value for the HD community as a tool to optimize novel therapeutic approaches aimed at modulating HTT protein levels.
Publisher: Oxford University Press (OUP)
Date: 20-08-2016
DOI: 10.1093/BRAIN/AWW212
Publisher: Wiley
Date: 21-05-2002
DOI: 10.1002/ANA.10208
Abstract: Beta-secretase cleavage represents the first step in the generation of Abeta polypeptides and initiates the amyloid cascade that leads to neurodegeneration in Alzheimer's disease. By comparative Western blot analysis, we show a 2.7-fold increase in protein expression of the beta-secretase enzyme BACE in the brain cortex of Alzheimer's disease patients as compared to age-matched controls. Similarly, we found the levels of the amyloid precursor protein C-terminal fragment produced by beta-secretase to be increased by nearly twofold in Alzheimer's disease cortex.
Publisher: American Medical Association (AMA)
Date: 10-2014
DOI: 10.1001/JAMADERMATOL.2014.635
Abstract: Mitotic rate is now recognized as having independent prognostic significance in melanoma survival. However, its clinicopathologic associations have not been the focus of any previous study. To identify a set of patient and tumor characteristics associated with high-mitotic-rate melanoma with the aim of facilitating the earlier detection of aggressive primary invasive melanoma. Cross-sectional study of patients from a multidisciplinary melanoma clinic based in a public hospital. A total of 2397 cases from January 2006 to December 2011 were reviewed by the Victorian Melanoma Service, and 1441 patients with 1500 primary invasive melanomas were included in the study. Mitotic rate was measured as number of mitoses per mm2 and analyzed as ordered categories (0, <1, 1 and 1-4 mm: OR, 4.5 95% CI, 3.2-6.1 >4 mm: OR, 12.6 95% CI, 7.5-21.1), and ulceration (OR, 2.0 95% CI, 1.5-2.7). These histopathologic features, along with amelanosis and rate of growth, remained as significant associations with high mitotic rate in the overall multivariate analysis. High-mitotic-rate primary cutaneous melanoma is associated with aggressive histologic features and atypical clinical presentation. It has a predilection for the head and neck region and is more likely to be seen in elderly men with a history of cumulative solar damage who present clinically with rapidly developing disease.
Publisher: Canadian Science Publishing
Date: 07-2007
DOI: 10.1139/Y07-065
Abstract: Bleomycin-induced lung fibrosis in mice reproduces some key features of pulmonary fibrosis in humans including alveolar inflammation, myofibroblast proliferation, and collagen deposition. Glucocorticoids have been used as first-line therapy for the treatment of lung fibrosis, although their clinical efficacy is equivocal. We examined the effect of the glucocorticoid, methylprednisolone (MP), and the estrogen metabolite, 2-methoxyestradiol (2MEO) on bleomycin-induced bronchoalveolar inflammation, fibrosis, and changes in lung function. The characterization of the time-course of the bleomycin-induced fibrosis indicated that lung dry mass and hydroxyproline content showed less variance than histopathological assessment of fibrosis. The bleomycin-induced increases in bronchoalveolar lavage (BAL) fluid cell number and protein levels were not significantly influenced by treatment with either MP (1 mg·(kg body mass) –1 ·day –1 , i.p.) or 2MEO (50 mg·(kg body mass) –1 ·day –1 , i.p.). Lung fibrosis, measured histopathologically or by hydroxyproline content, was not significantly influenced by either MP or 2MEO treatment, whereas the latter agent did reduce the increment in lung dry mass. The enlargement of alveolar airspaces and the decline in lung compliance were exacerbated by MP treatment. These data suggest that bleomycin-induced pulmonary fibrosis is resistant to inhibition by concurrent treatment with either glucocorticoids or 2MEO.
Publisher: Informa UK Limited
Date: 08-10-2009
DOI: 10.3109/10428190903288456
Abstract: Neurologic relapse of systemic diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The existing literature about this specific entity is very limited. We present a retrospective analysis of patients with neurological relapse of DLBCL and correlate the outcome according to the disease stage at autologous stem cell transplantation (ASCT) and the cell of origin phenotype. Totally, 11 patients with neurologic relapse of DLBCL underwent ASCT, seven in complete remission (CR) and four with active disease. The conditioning regimens included LACE (six), BEAM (two), and Bu/Mel (three). Ten patients relapsed after ASCT. All patients with CNS relapse died of progressive disease. Patients with systemic relapse were salvaged by further treatment. The median disease free survival (DFS) and overall survival (OS) for patients in CR at ASCT is far superior than those with active disease at ASCT (24 and 33 months versus 3 and 5 months, respectively). For patients undergoing ASCT in CR, the germinal centre (GC) phenotype is associated with a superior DFS and OS as compared to non GC phenotype (36 and 40 months versus 3.5 months and 5 months, respectively). Patients with neurological relapse of DLBCL have a poor outcome after ASCT the outcome is worse for patients with non-GC phenotype irrespective of the disease stage at ASCT.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-06-2022
DOI: 10.1161/CIRCULATIONAHA.121.057006
Abstract: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)–based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92 sensitivity, 93% specificity, 92% negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7 EMB, n=8 P =0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%] odds ratio, 0.091 P =0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%] odds ratio, 0.192 P =0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. HREC/13/SVH/66 and HREC/17/SVH/80. Australian New Zealand Clinical Trials Registry: ACTRN12618000672257.
Publisher: Springer Science and Business Media LLC
Date: 26-01-2018
Publisher: Wiley
Date: 14-05-2012
DOI: 10.1002/JMV.23236
Abstract: Histological parameters were assessed in liver biopsies (n = 48) performed in patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in order to evaluate factors which were associated with significant liver disease. Necroinflammation and fibrosis was scored by the Ishak classification system, and binary logistic regression analysis was used to assess HIV and antiretroviral-related determinants of necroinflammation and fibrosis. A total of 46 biopsies were included 33 were from HIV-positive patients co-infected with HCV and 15 biopsies were from HIV-positive patients co-infected with HBV. One HIV-positive patient was co-infected with HBV and HCV. Median biopsy inflammatory grade for the cohort was 8.5 (IQR 6-10), the median fibrosis Stage 2 (IQR 1.8-4), and the median steatosis score was 1 (IQR 0-2). At the univariate level, HIV-related variables that were significantly associated with more severe biopsy changes were higher HIV RNA at the time of biopsy (associated with inflammatory Grade 10+ P = 0.018) and any exposure to didanasine (ddI) or stavudine (D4T associated with fibrosis Stage 3+ P = 0.022). HIV RNA at the time of biopsy remained significant at the multivariate level. Patients with HIV hepatitis co-infection in this cohort had surprisingly mild changes in liver histology, and there were no statistically significant differences between biopsy results in HBV compared to HCV co-infection. The association between HIV RNA and necroinflammation supports current recommendations for earlier initiation of HAART in patients with HIV-hepatitis co-infection.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JAAD.2018.04.045
Abstract: The recognition and diagnosis of clinically amelanotic or hypomelanotic melanoma is a challenge. This study aimed to examine the anatomic distribution and risk factors associated with clinically amelanotic or hypomelanotic melanoma and compare the survival of patients with clinically amelanotic or hypomelanotic melanoma with that of patients with pigmented melanoma. A prospective cohort study of all cases of primary invasive melanoma managed at a tertiary referral center was performed. There were a total of 3913 invasive melanomas, and 384 (9.8%) were clinically amelanotic or hypomelanotic. Skin phototype I red as well as blonde hair color actinic keratoses nodular, desmoplastic, and lentigo maligna subtype increased Breslow thickness and mitoses were independently associated with amelanotic or hypomelanotic melanoma (P < .05). After adjustment for subtype and thickness, the face, ears, lateral aspect of the neck, upper portion of the arm, posterior aspect of the forearm, dorsal aspect of the hand, and anterior aspect of the lower portion of the leg were associated with increased odds of amelanotic or hypomelanotic melanoma when compared with the upper portion of the back (P < .05). Mortality risk from melanoma appeared greater for amelanotic or hypomelanotic melanoma than for pigmented melanoma (hazard ratio, 1.5 95% confidence interval, 1.1-2.1) but was similar once Breslow thickness was taken into account. Single tertiary referral center. Although clinically amelanotic or hypomelanotic melanoma can occur on all body sites, it is more common on chronically sun-exposed areas. Clinicians should have an increased index of suspicion in patients with a sun-sensitive skin phenotype, red hair, and associated actinic keratoses.
Publisher: Oxford University Press (OUP)
Date: 20-08-2012
DOI: 10.1002/STEM.1167
Abstract: Monoclonal antibodies against cell surface markers are powerful tools in the study of tissue regeneration, repair, and neoplasia, but there is a paucity of specific reagents to identify stem and progenitor cells in tissues of endodermal origin. The epitope defined by the GCTM-5 monoclonal antibody is a putative marker of hepatic progenitors. We sought to analyze further the distribution of the GCTM-5 antigen in normal tissues and disease states and to characterize the antigen biochemically. The GCTM-5 epitope was specifically expressed on tissues derived from the definitive endoderm, in particular the fetal gut, liver, and pancreas. Antibody reactivity was detected in subpopulations of normal adult biliary and pancreatic duct cells, and GCTM-5-positive cells isolated from the nonparenchymal fraction of adult liver expressed markers of progenitor cells. The GCTM-5-positive cell populations in liver and pancreas expanded greatly in numbers in disease states such as biliary atresia, cirrhosis, and pancreatitis. Neoplasms arising in these tissues also expressed the GCTM-5 antigen, with pancreatic adenocarcinoma in particular showing strong and consistent reactivity. The GCTM-5 epitope was also strongly displayed on cells undergoing intestinal metaplasia in Barrett's esophagus, a precursor to esophageal carcinoma. Biochemical, mass spectrometry, and immunochemical studies revealed that the GCTM-5 epitope is associated with the mucin-like glycoprotein FCGBP. The GCTM-5 epitope on the mucin-like glycoprotein FCGBP is a cell surface marker for the study of normal differentiation lineages, regeneration, and disease progression in tissues of endodermal origin.
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/02688690600852647
Abstract: A 70-year-old woman developed disseminated intravascular coagulation (DIC) during a craniotomy for a parasagittal anaplastic/malignant meningioma. This was successfully treated with rapid resection of the tumour and haematological replacement, but a poor neurological outcome resulted. The tumour was demonstrated to express tissue factor, an important causative factor in other tumour associated DIC and previously shown to be expressed by malignant meningiomas. A link between the two is suggested.
Publisher: Canadian Urological Association Journal
Date: 11-03-2015
DOI: 10.5489/CUAJ.2174
Publisher: Wiley
Date: 23-07-2009
Publisher: Wiley
Date: 15-12-2003
DOI: 10.1046/J.1432-1033.2003.03936.X
Abstract: The presenilin proteins are required for intramembrane cleavage of a subset of type 1 membrane proteins including the Alzheimer's disease amyloid precursor protein. Previous studies indicate presenilin proteins form enzymatically active high molecular mass complexes consisting of heterodimers of N- and C-terminal fragments in association with nicastrin, presenilin enhancer-2 and anterior pharynx defective-1 proteins. Using Blue Native gel electrophoresis (BN/PAGE) we have studied endogenous presenilin 1 complex mass, stability and association with nicastrin, presenilin enhancer-2 and anterior pharynx defective-1. Solubilization of mouse or human brain membranes with dodecyl-d-maltoside produced a 360-kDa species reactive with antibodies to presenilin 1. Presenilin 1 complex levels were high in embryonic brain. Complex integrity was sensitive to Triton X-100 and SDS, but stable to reducing agent. Addition of 5 M urea caused complex dissolution and nicastrin to migrate as a subcomplex. Nicastrin and presenilin enhancer-2 were detected in the presenilin 1 complex following BN/PAGE, electroelution and second-dimension analysis. Anterior pharynx defective-1 was detected as an 18-kDa form and 9-kDa C-terminal fragment by standard SDS/PAGE of mouse tissues, and as a predominant 36-kDa band after presenilin 1 complex second-dimension analysis. Membranes from brain cortex of Alzheimer's disease patients, or from cases with presenilin 1 missense mutations, indicated no change in presenilin 1 complex mobility. Higher molecular mass presenilin 1-reactive species were detected in brain containing presenilin 1 exon 9 deletion mutation. This abnormality was confirmed using cells transfected with the same presenilin deletion mutation.
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.JOCN.2007.12.010
Abstract: We report the rare entity of an inverted papilloma arising from the sphenoid sinus that we expected to be a pituitary tumour on the basis of history, examination and pre-operative investigations, especially MRI appearance. Inverted sinonasal papilloma should be considered in the differential diagnosis of pituitary macroadenoma invading the sphenoid sinus.
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2013
DOI: 10.1158/1055-9965.EPI-13-0136
Abstract: Background: Adult weight is positively associated with postmenopausal breast cancer but few studies have investigated whether there are associations with weight and body mass index (BMI) in early adulthood, or subsequent weight change. Methods: A total of 14,441 postmenopausal women from the Melbourne Collaborative Cohort Study (MCCS) were followed for 16.5 years (mean) and 668 incident breast cancers were identified. Hazard ratios (HRs) were estimated using Cox regression. Results: Weight and BMI at 18 to 21 years were not associated with risk of any type of breast cancer and there was no variation by age. Women with the greatest increase in weight and BMI had higher risk at older ages [HR per 5 kg/m2 gain in BMI = 1.24 95% confidence interval (CI), 1.11–1.40], although the test for homogeneity by age was not significant. At older ages, the association was stronger for progesterone (PR) positive disease compared with PR negative disease (HR per 5 kg/m2 gain in BMI, 1.43 95% CI, 1.23–1.66 test for homogeneity by PR status, P & 0.01) and for diseases that were positive for both estrogen (ER) and PR (HR per 5 kg/m2 gain in BMI, 1.45 95% CI, 1.24–1.69 test for homogeneity by ER/PR status, P = 0.02). HRs were also greater for HER2− and luminal A tumors, but the P values for homogeneity by tumor subgroups were not significant. Conclusion: Early adulthood weight is not associated with risk of postmenopausal breast cancer. Greater weight gain during adulthood might be associated with increased risk for older women (& years) and this association might vary by tumor hormone receptor status. Impact: Further studies need to investigate the impact of increase in weight during adulthood on postmenopausal breast cancer risk and the potential variation by age or tumor characteristics. Cancer Epidemiol Biomarkers Prev 22(8) 1409–16. ©2013 AACR.
Publisher: Wiley
Date: 06-1999
DOI: 10.1046/J.1471-4159.1999.0722479.X
Abstract: To study amyloid beta-protein (A beta) production and aggregation in vivo, we created two transgenic (Tg) mouse lines expressing the C-terminal 100 amino acids of human amyloid precursor protein (APP): Tg C100.V717F and Tg C100.WT. Western blot analysis showed that human APP-C100 and A beta were produced in brain and some peripheral tissues and A beta was produced in serum. Using antibodies specific for the A beta C terminus we found that Tg C100.V717F produced a 1.6-fold increase in A beta42/A beta40 compared with Tg C100.WT. Approximately 30% of total brain A beta (approximately 122 ng/g of wet tissue) was water-soluble. The remaining 70% of A beta partitioned into the particulate fraction and was completely sodium dodecyl sulfate-soluble. In contrast, human Alzheimer's disease brain has predominantly sodium dodecyl sulfate-insoluble A beta. Immunohistochemistry with an A beta(5-8) antibody showed that A beta or A beta-containing fragments accumulated intracellularly in the hippoc us of aged Tg C100.V717F mice. The soluble A beta levels in Tg brain are similar to those in normal human brain, and this may explain the lack of microscopic amyloid deposits in the Tg mice. However, this mouse model provides a system to study the intracellular processing and accumulation of A beta or A beta-containing fragments and to screen for compounds directed at the gamma-secretase activity.
Publisher: Elsevier BV
Date: 12-2014
Publisher: American Association for Cancer Research (AACR)
Date: 02-2010
DOI: 10.1158/1055-9965.EPI-09-0532
Abstract: Epidemiologic studies have consistently reported that endogenous steroid hormone levels are associated with postmenopausal breast cancer risk, but little is known on the associations by tumor grade, hormone receptor status, or age at diagnosis. We performed a case-cohort study of naturally postmenopausal women within the Melbourne Collaborative Cohort Study that included a random s le of 857 women and 197 breast cancer cases diagnosed during a mean of 9.2 years of follow-up. Concentrations of total estradiol, estrone sulfate, testosterone, DHEA sulfate, androstenedione, and sex hormone binding globulin were measured in plasma collected at baseline before diagnosis free estradiol plasma concentration was calculated. Cox regression was used to estimate associations adjusted for known and potential confounders. The HR for breast cancer comparing fourth and first quartiles was 1.44 [95% confidence interval (95% CI), 0.89-2.35] for total estradiol, 1.75 (95% CI, 1.06, 2.89) for free estradiol, 2.05 (95% CI, 1.24-3.37) for estrone sulfate, 1.25 (95% CI, 0.78-2.01) for testosterone, 1.41 (95% CI, 0.88-2.27) for DHEA sulfate, 1.49 (95% CI, 0.91-2.44) for androstenedione, and 0.33 (95% CI, 0.19-0.55) for sex hormone binding globulin. These associations did not differ by tumor grade and estrogen receptor rogesterone receptor status (all test for heterogeneity, P & 0.05). Risks associated with estrogen and androgen levels were stronger at older ages (test for interaction across age groups, P = 0.59 for total estradiol and P = 0.01 for testosterone). Our prospective study confirms earlier findings and suggests that the associations of endogenous hormones with postmenopausal breast cancer risk are independent of tumor grade, and hormone receptor status and might increase in strength with age. Cancer Epidemiol Biomarkers Prev 19(2) 492–502
Publisher: Elsevier BV
Date: 06-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-01-2016
DOI: 10.1212/CPJ.0000000000000215
Abstract: Diagnosis of ataxic disorders is an important clinical challenge upon which prognostication, management, patient solace, and, above all, the hope of future treatment all rely. Heritable diseases and the possibility of affected offspring carry the added burden of portending adverse health, social and financial ramifications. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited multisystem ataxia compromising cerebellar, vestibular, and sensory function. It is not uncommon, but despite early attempts the genetic defect is yet to be identified. As the search for the causative gene continues, we have found it useful to further define this syndrome in terms of its likely phenotype. We propose staged diagnostic criteria based on the identified pathology in CANVAS. We envisage that these criteria will aid the clinician in diagnosing CANVAS and the researcher in further elucidating this complex disorder.
Publisher: Informa UK Limited
Date: 02-2013
DOI: 10.1128/MCB.01016-12
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.EJON.2013.01.010
Abstract: Survival from rectal cancer has improved substantially. Understanding the consequences of treatment is important to optimise patient support and minimise impact on daily life. We aimed to define the long-term prevalence of pelvic dysfunction following curative rectal cancer surgery (+/- radiotherapy) within the context of overall quality of life. We evaluated bowel, urinary and sexual function and quality of life using three validated questionnaires in patients treated for rectal cancer. This group was compared to patients undergoing abdominal surgery without pelvic dissection for colon cancer during the same time period. The response rate was 57% (381/667) with a median time interval of 4.4 years. A subset of rectal patients documented persistent problems with faecal leakage (16%) requiring to alter daily activities (18%) always needing to wear a protective pad (17%) rarely or never emptying their bowels fully (31%) difficulty controlling the passage of gas (32%) and requiring to modify diet (30%). Altered bowel function was found to impact on overall quality of life. Men reported increased erectile function difficulties. Pre-operative radiotherapy was associated with increased defecation problems as was low level of anastomosis (≤6 cm). In keeping with emergent evidence, this study has quantified the extent of late adverse effects with a sub-set of rectal cancer patients reporting persistent bowel function problems. The implications are now to consider current follow-up services and to 'trial' new models of comprehensive assessment and interventions in patients who are 'at risk' of experiencing late adverse effects of treatment.
Publisher: Elsevier BV
Date: 1995
DOI: 10.1016/S0936-6555(05)80004-4
Abstract: Expounding the heterogeneity for ovarian cancer (OC) with the cognition in developmental biology might be helpful to search for robust prognostic markers and effective treatments. In the present study, we employed single-cell RNA-seq with ovarian cancers, normal ovary, and embryo tissue to explore their heterogeneity. Then the differentiation process of clusters was explored the pivotal cluster and markers were identified. Furthermore, the consensus clustering algorithm was used to explore the different clinical phenotypes in OC. At last, a prognostic model was construct and used to assess the prognosis for OCs. As a result, eight erse clusters were identified, and the similarity existed in some clusters between embryo and tumours based on their gene expression. Meaningfully, a subtype of malignant epithelial cluster, PEG10
Publisher: Springer Science and Business Media LLC
Date: 10-10-2014
DOI: 10.1038/NCOMMS5809
Publisher: Wiley
Date: 15-04-2018
DOI: 10.1111/PCMR.12702
Abstract: This study aimed to determine the frequency and concordance of BRAF and NRAS mutation in tumours arising in patients with multiple primary melanoma (MPM). Patients with MPM managed at one of three tertiary referral centres in Melbourne, Australia, from 2010 to 2015 were included. Incident and subsequent melanomas underwent mutation testing. Cohen's kappa (κ) coefficient assessed agreement between incident and subsequent primary melanomas for both BRAF and NRAS mutation status (mutant versus wild-type). Mutation testing of at least two primary tumours from 64 patients was conducted. There was poor agreement for both BRAF and NRAS mutation status between incident and subsequent melanomas (κ = 0.10, 95% CI -0.10 to 0.42 κ = 0.06, 95% CI -0.10 to 0.57, respectively). In view of the low concordance in BRAF mutation status between incident and subsequent melanomas, mutational analysis of metastatic tissue, rather than of a primary melanoma, in patients with MPM should be used to guide targeted therapy.
Publisher: Oxford University Press (OUP)
Date: 02-2009
DOI: 10.1086/595894
Publisher: Informa UK Limited
Date: 2001
DOI: 10.1080/146608201753275463
Abstract: The p75 neurotrophin receptor has been recognized as a death-signalling molecule under certain circumstances. Its role in motor neuron degeneration in amyotrophic lateral sclerosis (ALS) was analysed in SOD1-G93A transgenic mice and in spinal cords from human amyotrophic lateral sclerosis. The precise loss of motor neurons in SOD1-G93A transgenic mice from birth to adulthood was established using the unbiased fractionator/optical dissector neuronal counting technique. This study showed an early trend in the loss of lumbar motor neurons in SOD1-G93A mice, beginning at birth and progressing to a massive 80% reduction by 4 months of age, when the disease is severe. This study also found that the p75 neurotrophin receptor was expressed in lumbar motor neurons in symptomatic SOD1-G93A mice and in motor neurons in the cervical spinal cords of patients with ALS. The murine and human ALS data suggest that the p75 neurotrophin receptor may play a death-signalling role in the pathogenesis of motor neuron degeneration. The precise mechanism by which this receptor drives the apoptotic process, both in murine SOD1-G93A motor neuron degeneration and in human amyotrophic lateral sclerosis, remains to be determined.
Publisher: Wiley
Date: 12-05-2015
DOI: 10.1111/NEUP.12205
Publisher: Elsevier BV
Date: 02-2011
Publisher: Wiley
Date: 24-08-2010
DOI: 10.1111/J.1440-0960.2010.00682.X
Abstract: The recombinant human keratinocyte growth factor, palifermin, offers a potential means of reducing or preventing mucositis in patient undergoing intensive cancer treatments. This case report details the development of acral erythrodysaesthesia in one patient who underwent palifermin treatment prior to high-intensity re-induction chemotherapy for acute myeloid leukaemia.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 26-06-2014
DOI: 10.1038/NCOMMS5264
Publisher: Springer Science and Business Media LLC
Date: 22-09-2015
DOI: 10.1038/ONC.2014.303
Abstract: Glioblastoma is the most common and lethal primary malignant brain tumor in adults. The tumor suppressor gene PTEN is deleted, mutated or hypermethylated in more than 60% of glioblastoma cases resulting in hyperactivation of the phosphoinositide 3-kinase pathway, which leads to sustained PI(3,4,5)P3 signaling, and thereby hyperactivation of Akt and other effectors. PI(3,4,5)P3 is also hydrolyzed to PI(3,4)P2 by inositol polyphosphate 5-phosphatases such as SKIP, but the role this pathway has in glioblastoma is unknown. Microarray expression profiling of SKIP in human glioblastoma has revealed both increased and decreased SKIP gene expression. Here we have screened PTEN-deficient glioblastoma for SKIP protein expression by immunohistochemistry and report that SKIP expression is increased in some cases or decreased relative to normal brain. Using the U-87MG PTEN-deficient cell line we show that SKIP knockdown did not further enhance cell proliferation or survival. However, SKIP overexpression in U-87MG cells suppressed anchorage-independent cell growth and growth factor-induced PI(3,4,5)P3/Akt signaling. Although, SKIP knockdown did not affect cell proliferation or survival, cell migration was significantly retarded, associated with significantly increased PI(4,5)P2 signals, and decreased phosphorylation of the actin-regulatory protein cofilin, a PI(4,5)P2-binding protein. Notably, overexpression of SKIP also inhibited migration of U-87MG cells to a similar degree as observed with PTEN reconstitution, however, via distinct mechanisms. PTEN reconstitution promoted sustained lamellipodia generation and focal adhesion formation. In contrast, SKIP overexpression reduced sustained lamellipodia formation, talin incorporation into focal adhesions and recruitment of PI(4,5)P2-binding proteins to the plasma membrane. Notably, analysis of two independent ONCOMINE microarray data sets revealed a significant correlation between increased SKIP mRNA expression in glioblastoma and improved long-term survival. Therefore, SKIP expression in glioblastoma may affect the local invasion of PTEN-deficient tumors.
Publisher: Wiley
Date: 02-02-2004
DOI: 10.1002/JNR.20020
Abstract: The hemorphins are a family of opioid receptor-binding peptides originating from the beta-chain of hemoglobin and have been found at high levels within the central and peripheral nervous systems. In addition to opioid receptor binding, hemorphins have been shown to have a number of effects on the renin-angiotensin system, including inhibition of angiotensin-converting enzyme and angiotensin IV receptor binding. However, relatively few studies have examined the role of hemorphins in neurological diseases. Here we report the first study of hemorphins in Alzheimer's disease (AD) brains. Quantitative MALDI-TOF mass spectrometry was employed to assess levels of LVV and VV hemorphin-6 and -7 in 10 control and 10 AD brain tissue s les. LVV hemorphin-6 and total hemorphin levels were elevated in AD temporal neocortex but not in hippoc us, occipital lobe, or frontal lobe. The elevation of hemorphins is probably indicative of a vascular abnormality resulting from cerebral amyloid angiopathy associated with both neurodegenerative disease and aging.
Publisher: Wiley
Date: 19-10-2018
Publisher: Springer Science and Business Media LLC
Date: 14-10-2016
Publisher: Wiley
Date: 27-05-2004
DOI: 10.1002/ANA.20144
Publisher: American Medical Association (AMA)
Date: 09-2013
DOI: 10.1001/JAMANEUROL.2013.165
Abstract: Here we describe the unusual clinical and molecular-neuropathological profile of a case of Gerstmann-Sträussler-Scheinker disease associated with a novel prion protein (PRNP) gene mutation. This case report from the Australian National Creutzfeldt-Jakob Disease Registry concerns a 61-year-old British-born woman with no history of neurodegenerative disorder in first-degree relatives. Rapidly progressive dementia, altered behavior, and cerebellar ataxia dominated the clinical picture in the period immediately following minor elective surgery, with death 1 month later in an akinetic-mute state. Brain histopathological examination revealed neuronal loss, scant foci of spongiform change, and diffuse multicentric amyloid plaques, selectively immunoreactive for prion protein, within the cerebral and cerebellar cortices and deep gray matter. Tau immune-reactive neurofibrillary tangles and neuritic threads were present in the cerebral cortex. PRNP sequencing demonstrated a valine to glycine mutation at codon 176, with valine homozygosity at polymorphic codon 129. Western-blot analysis of frozen brain tissue displayed a nonclassic protease-resistant prion protein banding pattern, with a prominent approximately 8-kDa protease-resistant fragment. Reported is a proband with a novel PRNP mutation associated with neuropathologically confirmed Gerstmann-Sträussler-Scheinker disease displaying a somewhat unusual constellation of clinicopathological features, which overall subserve to further broaden an already erse phenotypic spectrum.
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.CGH.2007.02.022
Abstract: Interferon-based therapy can improve hepatic histology in chronic hepatitis C (CHC)-related cirrhosis but its effect on portal hypertension is unclear. The aims of this study were to investigate the effect of treatment with peginterferon alfa-2a and ribavirin on hepatic venous pressure gradient (HVPG) in CHC with compensated cirrhosis. Forty-seven patients with compensated biopsy examination-proven cirrhosis were recruited from 2 metropolitan teaching hospitals and were treated for 48 weeks with combination peginterferon alfa-2a 180 microg by subcutaneous injection weekly and ribavirin 800-1200 mg/day orally. A transjugular liver biopsy examination and HVPG measurement were performed at baseline, and 33 patients had a repeat HVPG measurement after 6 months of treatment-free follow-up evaluation. The overall sustained viral response (SVR) was 21%. Posttreatment there was a significant decrease in HVPG level in sustained responders compared with nonresponders (-2.1 +/- 4.8 vs 0.6 +/- 2.8 mm Hg P = .05). Among patients with portal hypertension, a higher proportion of sustained responders achieved a 20% or greater reduction in HVPG level compared with nonresponders (71% vs 20% P = .01). There was a significant association between a 20% or greater reduction in HVPG and both histologic response and SVR. Treatment with combination peginterferon plus ribavirin may produce clinically significant reductions in HVPG in patients with CHC-related cirrhosis who achieve an SVR.
Publisher: Springer Science and Business Media LLC
Date: 09-2010
Publisher: Springer Science and Business Media LLC
Date: 09-03-2015
DOI: 10.1038/NG.3242
Publisher: Elsevier BV
Date: 10-2015
Publisher: SAGE Publications
Date: 20-07-2016
Abstract: We report two patients with relapsing remitting multiple sclerosis (RRMS) on interferon (IFN) beta-1a treatment for more than 7 years who developed pulmonary arterial hypertension (PAH). Patient 1 developed severe PAH requiring lung transplantation. Histology showed typical proliferative lesions including plexiform lesions consistent with PAH. Patient 2 ceased IFN beta-1a, and their symptoms stabilised. Both cases highlight IFN beta-1a treatment as a potential risk factor for PAH. PAH needs to be considered as a diagnosis in patients on long-term IFN beta-1a treatment who develop new-onset respiratory symptoms.
Publisher: BMJ
Date: 29-03-2009
Abstract: Brain amyloid imaging using positron emission tomography (PET) is of increasing importance in the premortem evaluation of dementias, particularly in relation to Alzheimer disease (AD). The purpose of this study was to explore the premortem diagnostic utility of (11)C-PiB PET in sporadic Creutzfeldt-Jakob disease (CJD). Two patients, 72 and 59 years old, underwent evaluation for rapidly progressive cognitive decline, dying after illness durations of 5 and 7 months, respectively. As part of their comprehensive assessment, (18)F-FDG PET and (11)C-PiB PET studies were performed approximately 2-4 weeks prior to death, and the brain regional distributions compared with those from cohorts of healthy controls (HC) and AD patients. Routine investigations, including brain MRI scans, revealed changes typical of sporadic CJD, with the diagnosis confirmed at autopsy in both patients. The (18)F-FDG PET showed global hypometabolism in one patient and thalamic and frontal hypometabolism with unexpected hypermetabolism in the dentate nuclei of the cerebellum in the other. Neither patient displayed cerebral cortical (11)C-PiB PET retention above the levels observed in HC. No grey-matter (11)C-PiB retention was observed in two pathologically confirmed cases of typical sporadic CJD. We speculate that low PrP plaque density and small plaque size, as well as a relatively low affinity of the radioligand, explain the absence of (11)C-PiB retention. More studies to validate this hypothesis are warranted.
Publisher: Informa UK Limited
Date: 23-04-2012
DOI: 10.3109/00365521.2012.677955
Abstract: Type 2 diabetes mellitus (T2DM) is a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and subsequently hepatic fibrosis. Transient elastography (TE) is a rapid, reproducible non-invasive test that may be appropriate as a screening tool for the presence of hepatic fibrosis. Assess the utility of TE as a screening tool for the presence of hepatic fibrosis in a T2DM population with no known liver disease. T2DM patients without known liver disease were included. Patients were assessed with TE in addition to biochemical parameters. A successful TE evaluation could be obtained in 74 of 81 (91%) included subjects. Of these, 26 (35%) had a liver stiffness measurement (LSM) ≥ 7.65 kPa. Sixteen of these subjects had confirmatory liver biopsies with significant (≥ F2 fibrosis) present in 12 (75%) and cirrhosis diagnosed in 2 subjects. 15/16 (94%) had histological steatohepatitis. Compared with those with a lower LSM, subjects with an LSM ≥ 7.65 kPa had higher ALT levels (38.0 ± 21.7 vs 26.1 ± 11.1 U/L, p = 0.021) and increased prevalence of hepatic steatosis by ultrasound (85% vs 63%, p = 0.005). Significant hepatic fibrosis in the T2DM population is frequently under-recognized. TE may be a feasible tool for the screening of T2DM patients for the presence of hepatic fibrosis.
Publisher: Wiley
Date: 03-06-2008
DOI: 10.1002/MRM.21586
Abstract: We measured proton magnetic longitudinal (R(1)) and transverse (R(2)) relaxation rates at 1.4T, iron concentrations, water contents, and amyloid plaque densities in postmortem brain tissue s les from three Alzheimer's disease (AD), two possible AD, and five control subjects. Iron concentrations and R(1) were significantly higher in the temporal cortex region of our AD group compared to the controls. Frequency analyses showed that the observed trends of higher iron, R(1), and R(2) in AD gray matter regions were statistically significant. Simple regression models indicated that for AD and control gray matter the iron concentrations and water contents have significant linear correlations with R(1) and R(2). Multiple regression models based on iron concentrations and water contents were highly significant for all groups and tissue types and suggested that the effects of iron become more important in determining R(1) and R(2) in the AD s les. At 1.4T R(1) and R(2) are strongly affected by water content and to a lesser extent by variations in iron concentrations. The AD plaque density did not correlate with iron concentrations, water contents, R(1), or R(2), suggesting that increases in AD brain iron are not strongly related to the accumulation of amyloid plaques.
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/623241
Abstract: Alzheimer’s disease (AD) is the leading cause of dementia and represents a significant burden on the global economy and society. The role of transition metals, in particular copper (Cu), in AD has become of significant interest due to the dyshomeostasis of these essential elements, which can impart profound effects on cell viability and neuronal function. We tested the hypothesis that there is a systemic perturbation in Cu compartmentalization in AD, within the brain as well as in the periphery, specifically within erythrocytes. Our results showed that the previously reported decrease in Cu within the human frontal cortex was confined to the soluble ( P 0.05 ) and total homogenate ( P 0.05 ) fractions. No differences were observed in Cu concentration in erythrocytes. Our data indicate that there is a brain specific alteration in Cu levels in AD localized to the soluble extracted material, which is not reflected in erythrocytes. Further studies using metalloproteomics approaches will be able to elucidate the metabolic mechanism(s) that results in the decreased brain Cu levels during the progression of AD.
Publisher: Oxford University Press (OUP)
Date: 25-02-2016
DOI: 10.1093/BRAIN/AWV393
Publisher: Elsevier BV
Date: 05-1999
DOI: 10.1016/S0304-3940(99)00311-0
Abstract: A growing body of evidence suggests that the non-Abeta component of Alzheimer's disease amyloid precursor protein (NACP) or alpha-synuclein contributes to the neurodegenerative processes in Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In the present study antisera to the N terminus and the NAC domain of the alpha-synuclein protein were employed to elucidate the expression pattern in brains of patients with AD, PD, DLB and control specimen. Alpha-synuclein exhibited an overall punctuate expression profile compatible with a synaptic function. Interestingly, while Lewy bodies were strongly immunoreactive, none of the alpha-synuclein antisera revealed staining in mature beta-amyloid plaques in AD. These observations suggest that alpha-synuclein does not contribute to late neurodegenerative processes in AD brains.
Publisher: Wiley
Date: 15-02-2012
DOI: 10.1111/J.1365-2559.2011.04146.X
Abstract: Previous studies have indicated that expression of calcitonin receptor (CTR) could be induced in a proinflammatory environment. In the present study, CTR-immunoreactivity (CTR-ir) was investigated in brain tissue from patients with glioblastoma multiforme (GBM). In immunohistochemical analysis of GBM s les, tissues with complex glomeruloid structures surrounded by malignant cells were analysed for CTR-ir using anti-human CTR antibodies generated against two separate epitopes of CTR. CTR-ir was associated predominantly with glial cells. Regions with CTR-ir cells were found in 12 of 14 GBM tumours (P < 0.05). Using confocal microscopy, CTR-ir cells were identified that were also positive for glial fibrillary acidic protein, nestin and CD133. Antibodies were verified using immunoblots and confocal microscopy of the Cercopithecus aethiops(COS)-7 transfectants. Immunoblots of membrane preparations from the CTR-positive cell lines demonstrated a major band (≈ 67 kDa) and minor band (≈ 52 kDa), but the intensity was reversed for the GBM cell line A172. In cultured A172 cells, functional studies demonstrated calcitonin stimulation of adenylyl cyclase and inhibition of extracellular-regulated kinase (ERK)1/2 phosphorylation. The findings that (i) CTR was expressed by glioma cells in a majority of GBM tumours tested, (ii) CTR(+) /CD133(+) cells were identified and (iii) second messenger systems were functionally modified by calcitonin in A172 cells suggest that CTR might be a useful therapeutic target in GBM.
Publisher: Wiley
Date: 04-04-2006
DOI: 10.1111/J.1440-0960.2006.00243.X
Abstract: A 48-year-old man presented with a maculopapular truncal rash 9 days following intravenous hetamine use. He subsequently developed widespread bullae over his trunk and upper limbs. Treatment was initially commenced with intravenous hydrocortisone. A diagnosis of toxic epidermal necrolysis was made and the treatment was changed to intravenous immunoglobulin at a lower dose than requested. At the height of the reaction, there was 90% body surface area involvement with tri-mucosal involvement. His response to the intravenous immunoglobulin was poor and was complicated by infection with methicillin-resistant Staphylococcus aureus, Candida albicans and Pseudomonas aeruginosa. Gradual re-epithelialization took place over the next 6 weeks.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2009
DOI: 10.1007/S11682-009-9067-2
Abstract: With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aβ burden in vivo. Molecular neuroimaging techniques such as positron emission tomography (PET), in conjunction with related biomarkers in plasma and cerebrospinal fluid, are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). (11)C-PiB PET has proven useful in the discrimination of dementias, showing significantly higher PiB retention in grey matter of AD patients when compared with healthy controls or patients with frontotemporal dementia. (11)C-PiB PET also appears to be more accurate than FDG for the diagnosis of AD. Despite apparently underestimating the Aβ burden in the brain, (11)C-PiB PET is an optimal method to differentiate healthy controls from AD, matching histopathological reports in aging and dementia and reflecting the true regional density of Aβ plaques in cortical areas. High striatal Aβ deposition seems to be typical for carriers of familial forms of AD, whilst ApoE ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non- ε4 carriers. Characterization of the binding properties of PiB has shown that despite binding to other misfolded proteins in vitro, PiB is extremely selective for Aβ at the concentrations achieved during a PET scan. Aβ burden as assessed by PET does not correlate with measures of cognition or cognitive decline in AD. Approximately 30% of apparently healthy older people, and 50-60% of people with mild cognitive impairment, present with cortical (11)C-PiB retention. In these groups, Aβ burden does correlate with episodic memory and rate of memory decline. These observations suggest that Aβ deposition is not part of normal ageing, supporting the hypothesis that Αβ deposition occurs well before the onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations, coupled with different disease-specific tracers and biomarkers are required not only to confirm this hypothesis, but also to better elucidate the role of Αβ deposition in the course of Alzheimer's disease.
Publisher: Springer Science and Business Media LLC
Date: 2009
DOI: 10.1080/13550280903030125
Abstract: Increasing evidence supports early brain infection by human immunodeficiency virus (HIV). Definitive temporal studies determining when and within which brain cells viral DNA is present are lacking. This study utilized simian immunodeficiency virus (SIV)-infected macaques sacrificed at days 10, 21, 56, and 84 post inoculation. Laser-microdissection isolated pure perivascular macrophage, parenchymal microglia, and astrocyte populations. Nested polymerase chain reaction (PCR) and sequencing determined the presence and characteristics of SIV V3 and V1 env DNA from each population. At day 10, SIV DNA was detected in perivascular macrophage and astrocytes but not parenchymal microglia. gp41 expression was restricted to perivascular macrophage. At day 21, SIV DNA was not detected in any cell type. At day 56, SIV DNA was detectable in perivascular macrophage from one of two macaques, with no gp41 expression detected. At day 84 (morphologic and clinical encephalitis), SIV DNA was detected in all cell types, gp41 was only detected in perivascular macrophage and parenchymal microglia. The neurovirulent molecular clone, SIV/17E-Fr, was the only genotype identified in the brain cell populations. Early, productive brain SIV infection was transient and restricted to trafficking perivascular macrophage. During the nonencephalitic stage, there was a period of time when no SIV DNA could be detected in the brain cell populations. SIV was then seen to reenter the brain via infected perivascular macrophage, leading to productive infection of brain parenchymal macrophage/microglia with a terminal phase of encephalitis. These data challenge current notions of a HIV reservoir within latently infected, semipermanent brain cells and has significant implications for the timing and design of therapies to prevent HIV encephalitis (HIVE).
Publisher: Wiley
Date: 04-08-2014
DOI: 10.1111/PCMR.12295
Abstract: Activating mutations in the GTPase RAC1 are a recurrent event in cutaneous melanoma. We investigated the clinical and pathological associations of RAC1(P29S) in a cohort of 814 primary cutaneous melanomas with known BRAF and NRAS mutation status. The RAC1(P29S) mutation had a prevalence of 3.3% and was associated with increased thickness (OR=1.6 P = 0.001), increased mitotic rate (OR=1.3 P = 0.03), ulceration (OR=2.4 P = 0.04), nodular subtype (OR=3.4 P = 0.004), and nodal disease at diagnosis (OR=3.3 P = 0.006). BRAF mutant tumors were also associated with nodal metastases (OR=1.9 P = 0.004), despite being thinner at diagnosis than BRAF WT (median 1.2 mm versus 1.6 mm, P < 0.001). Immunohistochemical analysis of 51 melanomas revealed that 47% were immunoreactive for RAC1. Melanomas were more likely to show RAC1 immunoreactivity if they were BRAF mutant (OR=5.2 P = 0.01). RAC1 may therefore be important in regulating the early migration of BRAF mutant tumors. RAC1 mutations are infrequent in primary melanomas but may accelerate disease progression.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-09-2012
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.HEALUN.2008.01.005
Abstract: Pulmonary lymphangioleiomyomatosis (PLAM) is an indication for lung transplantation (LTx). Angiomyolipomas occur in approximately 50% to 60% of patients with PLAM. We describe a patient presenting with hemoptysis post-LTx for PLAM. Computed tomography (CT) scan demonstrated no pulmonary abnormality, but identified a retroperitoneal mass confirmed as angiomyolipoma by CT-guided core biopsy. Based on experimental work that rapamycin may inhibit angiomyolipoma cells, we commenced the patient on low-dose rapamycin. She had no adverse reactions and follow-up CT scan after 7 months demonstrated almost complete resolution of the tumor. This suggests a role for rapamycin in routine post-LTx immunosuppression for PLAM.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.NMD.2017.04.011
Abstract: Autosomal dominant mutations of DYNC1H1 cause a range of neurogenetic diseases, including mental retardation with cortical malformations, hereditary spastic paraplegia and spinal muscular atrophy. Using SNP array, linkage analysis and next generation sequencing, we identified two families and one isolated proband sharing a known spinal muscular atrophy, lower extremity predominant (SMALED) causing mutation DYNC1H1 c.1792C>T, p.Arg598Cys, and another family harbouring a c.2327C>T, p.Pro776Leu mutation. Here, we present a detailed clinical and pathological examination of these patients, and show that patients with DYNC1H1 mutations may present with a phenotype mimicking a congenital myopathy. We also highlight features that increase the phenotypic overlap with BICD2, which causes SMALED2. Serial muscle biopsies were available for several patients, spanning from infancy and early childhood to middle age. These provide a unique insight into the developmental and pathological origins of SMALED, suggesting in utero denervation with reinnervation by surrounding intact motor neurons and segmental anterior horn cell deficits. We characterise biopsy features that may make diagnosis of this condition easier in the future.
Publisher: Springer Science and Business Media LLC
Date: 05-2018
Publisher: Informa UK Limited
Date: 1991
DOI: 10.3109/02688699109002864
Abstract: Neurocytoma has only recently been recognized as a distinct pathological entity. Previously a rare tumor, it is now being recognized with increasing frequency. It typically presents in an intraventricular location in young adults. Many neurocytomas were originally diagnosed by light microscopy as oligodendrogliomas. More recently they have been shown to have ultrastructural and immunohistochemical features of neuronal differentiation. This paper presents two cases of intraventricular neurocytomas and reviews the recent literature.
Publisher: Wiley
Date: 07-2002
Publisher: Springer Science and Business Media LLC
Date: 25-01-2013
DOI: 10.1007/S00401-013-1083-Z
Abstract: The formation of low-order oligomers of β-amyloid (Aβ) within the brain is widely believed to be a central component of Alzheimer's disease (AD) pathogenesis. However, despite advances in high-throughput and high-resolution techniques such as xMAP and mass spectrometry (MS), investigations into these oligomeric species have remained reliant on low-resolution Western blots and enzyme-linked immunosorbent assays. The current investigation compared Aβ profiles within human cortical tissue using sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis (PAGE), xMAP and surface enhanced laser desorption/ionization time-of-flight MS and found that whilst there was significant correlation across the techniques regarding levels of monomeric Aβ, only SDS-PAGE was capable of detecting dimeric isoforms of Aβ. The addition of synthetic di-tyrosine cross-linked Aβ(1-40)Met(35)(O) to the AD tissue demonstrated that the MS methodology was capable of observing dimeric Aβ at femto-molar concentrations, with no noticeable effect on monomeric Aβ levels. Focus turned to the association between SDS-PAGE and levels of observable dimeric Aβ within the AD brain tissue. These investigations revealed that increased levels of dimeric Aβ were observed with increasing concentrations of SDS in the s le buffer. This finding was subsequently confirmed using synthetic Aβ(1-42) and suggests that SDS was inducing the formation of dimeric Aβ. The findings that SDS promotes Aβ dimerization have significant implications for the putative role of low-order oligomers in AD pathogenesis and draw into question the utility of oligomeric Aβ as a therapeutic target.
Publisher: Wiley
Date: 19-04-2005
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.MCN.2009.07.013
Abstract: Cholesterol, an essential component of cell membranes, plays an important role in the maintenance of cellular homeostasis and transmembrane communication within and between cellular compartments. In the brain that contains the highest levels of cholesterol in the body, cholesterol traffic occurs between nerve cells and between intracellular organelles in neurons to subserve normal brain function. Whereas glial cells produce the largest quantities of cholesterol, neurons also acquire cholesterol synthesized by astrocytes. The intracellular organelle endosomes and lysosomes receive and distribute cholesterol through the endocytic and retrograde transport pathways. However, deregulated cholesterol trafficking appears to be involved in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD) and Niemann-Pick disease type C (NPC) diseases. Under the pathological conditions of these neurodegenerative diseases, aberrant molecular interactions or particular depositions of cholesterol have been observed as critical causes to precipitate neuronal cell death. Here, we review the recent advances in terms of the role of cholesterol in healthy brain and molecular mechanisms of cholesterol involvement in AD, PD and NPC diseases. We discuss the different lines of evidence supporting different models of anomalous intracellular cholesterol trafficking with emphasis on cholesterol interactions with alpha-synuclein, NPC1 and NPC2 in AD, PD and NPC.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.NEUROIMAGE.2016.05.057
Abstract: Iron deposition in the brain is a feature of normal aging, though in several neurodegenerative disorders, including Alzheimer's disease, the rate of iron accumulation is more advanced than in age-matched controls. Using laser ablation-inductively coupled plasma-mass spectrometry imaging we present here a pilot study that quantitatively assessed the iron content of white and gray matter in paraffin-embedded sections from the frontal cortex of Alzheimer's and control subjects. Using the phosphorus image as a confirmed proxy for the white/gray matter boundary, we found that increased intrusion of iron into gray matter occurs in the Alzheimer's brain compared to controls, which may be indicative of either a loss of iron homeostasis in this vulnerable brain region, or provide evidence of increased inflammatory processes as a response to chronic neurodegeneration. We also observed a trend of increasing iron within the white matter of the frontal cortex, potentially indicative of disrupted iron metabolism preceding loss of myelin integrity. Considering the known potential toxicity of excessive iron in the brain, our results provide supporting evidence for the continuous development of novel magnetic resonance imaging approaches for assessing white and gray matter iron accumulation in Alzheimer's disease.
Publisher: Society for Neuroscience
Date: 06-05-2019
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JOCN.2018.06.031
Abstract: Hemangiopericytomas are rare mesenchymal tumors with propensity to recur locally and metastasize. We report the unique case of a fifty-five-year-old male with recurrence of a previously resected craniocervical hemangiopericytoma presenting with obstructive hydrocephalus secondary to new metastatic cerebellar deposits. Emergent surgical resection of the cerebellar hemangiopericytomas was performed prior to adjuvant radiotherapy. Hemangiopericytomas are rare but important differentials for craniocervical junction lesions. Gross total resection remains the cornerstone of management with post-operative radiotherapy and chemotherapy as potential adjuncts. Tumors located in deep regions pose complex management challenges as safe maximal excision may be limited by proximal eloquent structures.
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.JOCN.2005.06.015
Abstract: A case of rippling muscle disease is presented and features of this rare condition, and its association with caveolin-3 are discussed.
Publisher: Wiley
Date: 03-03-2014
DOI: 10.1111/BJH.12794
Publisher: AMPCo
Date: 03-2013
DOI: 10.5694/MJA12.11798
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
DOI: 10.1007/S10048-016-0480-6
Abstract: Progressive supranuclear palsy is a sporadic neurodegenerative disorder. Genetic, environmental, and possibly epigenetic factors contribute to disease. In order to better understand the potential role of epigenetic changes in progressive supranuclear palsy, we investigated whether some microRNAs and their target genes are dysregulated. We analyzed expression of 372 well-characterized microRNAs in forebrains of a total of 40 patients and of 40 controls using TaqMan arrays and SYBR Green quantitative real-time PCR. The exploratory cohort included forebrains from 20 patients and 20 controls provided by the Erasmus Medical Centre in Rotterdam, Netherlands. Confirmatory s les were from Jacksonville, Florida, and from Melbourne, Australia. Both microRNA profiling and SYBR Green quantitative real-time PCR revealed significant upregulation of miR-147 (miR-147a) and miR-518e in the exploratory cohort. Highly increased expression of these two microRNAs was validated in the confirmatory s les. Target genes of miR-147a (NF1, ACLY, ALG12) and of miR-518e (CPEB1, JAZF1, RAP1B) were repressed in patients' forebrains. The results suggest that dysregulation of specific microRNAs contributes to disease by repressing target genes involved in various cellular functions.
Publisher: Wiley
Date: 06-1994
Abstract: The major diagnostic histopathological features of moderate to severe Alzheimer's disease (AD) are amyloid rich neurofibrillary tangles (NFTs) and neuritic plaques (NPs) containing beta A4 peptide. As the frequency of stereotactic brain biopsies is increasing, the diagnostic cytological features of AD are of relevance. Our study presents the brain smear features of five autopsied patients with moderate to severe AD both clinically and pathologically. NFTs and NPs were identified in 100% of smears. Amyloid neuropil threads (NTs), a more recently identified hallmark of AD, were also seen in all smears. Segmental beta A4 peptide deposition within vessels, clustering of plaques around capillaries, and NTs were more obvious by the smear technique than in histological sections.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2014
Publisher: Oxford University Press (OUP)
Date: 13-01-2017
DOI: 10.1111/CED.13030
Abstract: Linear IgA bullous dermatosis (LABD) is a subepidermal autoimmune bullous disease characterized by linear IgA deposition at the basement membrane zone, which is visualized by direct immunofluorescence. Patients with LABD typically present with widespread vesicles and bullae however, this is not necessarily the case, as the clinical presentation of this disease is heterogeneous. LABD clinically presenting as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is an infrequent, yet well-described phenomenon. Most cases of LABD are idiopathic, but some cases are drug-induced. Multiple drugs have been implicated in the development of LABD. We report a case of piperacillin-tazobactam-induced LABD presenting clinically as SJS/TEN overlap. This is the first reported case of a strong causal association between piperacillin-tazobactam and the development of LABD.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2014
DOI: 10.1038/NCOMMS4756
Abstract: Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former are not mutually exclusive with TP53 mutations or MDM2 lification, showing that CDKN1A dysfunction is not simply an alternative mechanism for p53 pathway inactivation. We find strong positive associations between higher tumour stage/grade and greater clonal ersity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater ersity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression.
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0006-3223(03)00075-1
Abstract: It is unclear whether altered expression of a specific isoform of apolipoprotein E (apoE) is associated with the pathology of schizophrenia. To address whether apoE may be involved in the pathology of schizophrenia, we measured the genotypic and allelic frequency of polymorphisms in its gene and transcriptional regulatory region in DNA from Brodmann's area (BA) 9 obtained postmortem from schizophrenic and control subjects as well as its levels in the same tissue using Western blot analysis. The genotypic or allelic frequencies of any polymorphism studied did not vary between diagnostic cohorts. There was a significant increase in the levels of apoE protein in BA 9 from the schizophrenic subjects (Mean +/- SEM: 270 +/- 8.3 vs. 238 +/- 7.1 ng apoE/mg protein, p =.008) and a decrease in tissue from an analogous cortical region from rats treated with haloperidol compared with vehicle-treated animals (50 +/- 6.4 vs. 116 +/- 9.2 ng apoE/mg protein p =.0002). These data support the hypothesis that increased levels of apoE may be associated with the pathology of schizophrenia and that antipsychotic drugs decrease apoE levels as part of their therapeutic actions.
Publisher: Elsevier BV
Date: 09-2001
Publisher: Springer Science and Business Media LLC
Date: 06-10-2015
Publisher: Wiley
Date: 12-2012
DOI: 10.1111/IMJ.12000
Abstract: We report a case of a 75-year-old male with indolent chronic lymphocytic leukaemia (CLL) for 8 years, who presented with a 6-month history of a painful, zosteriform eruption in a T3-4 distribution that evolved into an unusual crop of papular nodules. Upon biopsy and immunostaining of these lesions CLL was proven consistent with leukaemia cutis related to varicella-zoster virus reactivation. In the absence of other treatment indices, he was commenced on chlorambucil with successful resolution of both his pain and the lesions.
Publisher: BMJ
Date: 09-2003
Abstract: Hereditary diffuse leucoencephalopathy with spheroids (HDLS) is a rare inherited progressive leucoencephalopathy characterised by giant neuroaxonal swellings (spheroids) within the CNS white matter. The case is reported of a 45 year old woman with a rapidly progressive fulminant illness course characterised by progressive cognitive decline with depressive features. A presumed dominant inheritance pattern was elicited. This report reviews the literature on HDLS and the relation of this disorder to other conditions with giant neuroaxonal swellings.
Publisher: Oxford University Press (OUP)
Date: 30-10-2012
Abstract: The relationship between latent JC polyomavirus (JCV) infection and progressive multifocal leukoencephalopathy (PML) remains unclear. In this study, JCV DNA was quantified by real-time polymerase chain reaction (qPCR) in brain and kidney tissue from patients without PML. Immunosuppressed patients had significantly higher JCV DNA levels in brain, compared with immunocompetent patients (P = .001). An inverse relationship was observed between CD4(+) T-cell counts and qPCR-determined brain JCV load among patients with HIV infection (r(2) = -0.9 P = .01 n = 7). Higher kidney JCV DNA load was strongly associated with higher brain JCV DNA load (Spearman ρ = 0.65 P = .004 n = 18). These findings highlight the importance of latent JVC brain infection to the pathogenesis of PML.
Publisher: Elsevier BV
Date: 07-1997
DOI: 10.1016/S0197-4580(97)00061-4
Abstract: The consensus recommendations for the post mortem diagnosis Alzheimer's disease (AD) highlight the difficulties in establishing a pathological diagnosis in brains from clinically demented in iduals with both certainty and uniformity. There is, however, a need for diagnostic guidelines that are relatively simple, inexpensive, and adaptable to general pathologists and different laboratories. The current Consortium to Establish a Registry for Alzheimer's disease (CERAD) criteria and the recommendations in the consensus document giving three probabilistic categories for diagnosis go a long way towards establishing a uniform approach for the diagnosis of AD. However, more uniformity could be adopted in the topography of sectioning to enhance diagnostic and future research comparisons. We also recommend that immunohistochemistry for beta A4 (A beta) amyloid and tau-reactive neurofibrillary changes, in addition to hematoxylin and eosin stains, should become the basis for histological diagnosis. We agree with the guidelines concerning documentation of all AD changes. Until a clearer understanding of the early changes of AD is established, strict observation and recording are the pathologists' best diagnostic skills. The ill-defined diagnostic areas of AD continue to prompt the need for a new method of detection of the underlying pathologic process.
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.IJROBP.2005.12.002
Abstract: To investigate radiation necrosis in patients treated for glioma in terms of incidence, outcomes, predictive and prognostic factors. Records were reviewed for 426 patients followed up until death or for at least 3 years. Logistic regression analysis was performed to identify predictive and prognostic factors. Multivariate survival analysis was conducted using Cox proportional hazards regression. Separate analyses were performed for the subset of 352 patients who received a biologically effective dose (BED) > or =85.5 Gy2 (> or =45 Gy/25 fractions) who were at highest risk for radionecrosis. Twenty-one patients developed radionecrosis (4.9%). Actuarial incidence plateaued at 13.3% after 3 years. In the high-risk subset, radiation parameters confirmed as risk factors included total dose (p < 0.001), BED (p < 0.005), neuret (p < 0.001), fraction size (p = 0.028), and the product of total dose and fraction size (p = 0.001). No patient receiving a BED <96 Gy2 developed radionecrosis. Subsequent chemotherapy significantly increased the risk of cerebral necrosis (p = 0.001) even when adjusted for BED (odds ratio [OR], 5.8 95% confidence interval [CI], 1.6-20.3) or length of follow-up (OR, 5.4 95% CI, 1.5-19.3). Concurrent use of valproate appeared to delay the onset of necrosis (p = 0.013). The development of radionecrosis did not affect survival (p = 0.09). Cerebral necrosis is unlikely at doses below 50 Gy in 25 fractions. The risk increases significantly with increasing radiation dose, fraction size, and the subsequent administration of chemotherapy.
Publisher: MDPI AG
Date: 16-07-2020
DOI: 10.3390/CELLS9071709
Abstract: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the deposition of misfolded proteins in the motor cortex and motor neurons. Although a multitude of ALS-associated mutated proteins have been identified, several have been linked to small extracellular vesicles such as exosomes involved in cell−cell communication. This study aims to determine the proteome of extracellular vesicles isolated from the motor cortex of ALS subjects and to identify novel ALS-associated deregulated proteins. Motor cortex extracellular vesicles (MCEVs) were isolated from human postmortem ALS (n = 10) and neurological control (NC, n = 5) motor cortex brain tissues and the MCEVs protein content subsequently underwent mass spectrometry analysis, allowing for a panel of ALS-associated proteins to be identified. This panel consists of 16 statistically significant differentially packaged proteins identified in the ALS MCEVs. This includes several upregulated RNA-binding proteins which were determined through pathway analysis to be associated with stress granule dynamics. The identification of these RNA-binding proteins in the ALS MCEVs suggests there may be a relationship between ALS-associated stress granules and ALS MCEV packaging, highlighting a potential role for small extracellular vesicles such as exosomes in the pathogenesis of ALS and as potential peripheral biomarkers for ALS.
Publisher: The Royal Society
Date: 27-11-2008
Abstract: A comparison of the pathological profiles of two spongiform encephalopathies with a similar presumptive route of infection was performed. Archival kuru and recent variant Creutzfeldt–Jakob disease (vCJD) cases reveal distinct lesional differences, particularly with respect to prion protein, suggesting that the strain of agent is important in determining the phenotype. Genotype analysis of the polymorphism on codon 129 reveals (in conjunction with updated information from more kuru cases) that all three genotypes (VV, MV and MM (where M is methionine and V is valine)) are detected in kuru with some preference for MM homozygosity. The presence of valine does not therefore appear to determine peripheral selection of PrP CJD . vCJD remains restricted to date to MM homozygosity on codon 129. It remains to be determined whether this genotype is dictating a shorter incubation period.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2012
DOI: 10.1038/BJC.2012.418
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.NBD.2008.02.009
Abstract: The unfolded protein response (UPR) is induced at symptom onset and disease end stage in rodent models of familial amyotrophic lateral sclerosis (ALS) that express superoxide dismutase (SOD1) mutations. However, ninety percent of human ALS is sporadic and mutations in SOD1 account for only 2% of total ALS. Here we show that a full UPR, including induction of stress sensor kinases, chaperones and apoptotic mediators, is also present in spinal cords of human patients with sporadic disease. Furthermore, the UPR chaperone protein disulphide isomerase (PDI) was present in CSF and was aggregated and widely distributed throughout the motor neurons of these patients. We also show up-regulation of UPR prior to the onset of symptoms in SOD1 rodents, implying an active role in disease. This study offers new insights into pathogenesis, placing ER stress onto a generic pathophysiology for ALS.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.NMD.2009.11.015
Abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disorder characterized by progressive deterioration of motor neurons in the spinal cord, brainstem, and cerebral cortex. Matrix metalloproteinase-9 (MMP-9) is proposed to be a biomarker for ALS due to a potential pathological role in the disease. However, despite numerous studies, it is still unclear whether there is a direct correlation between MMP-9 expression in serum and progression of disease. Therefore, we used a TgSOD1(G93A) mouse with a low transgene copy number. This model shows slow disease progression analogous to human ALS and provides a useful model to study biomarker expression at different stages of disease. Using zymography, we found that serum MMP-9 activity was significantly elevated in animals showing early signs of disease when compared to the younger, pre-symptomatic animals. This was followed by a decrease in MMP-9 activity in TgSOD1(G93A) mice with end-stage disease. These results were confirmed in serum of a high copy number strain of TgSOD1(G93A) mice with rapid progression. MMP-9 expression was changed accordingly in spinal motor neurons, glia and neuropil, suggesting a spinal cord contribution to blood MMP-9 activity. Serum MMP-2 activity followed a similar profile as the MMP-9 in these two models. These data indicate that circulating MMP-9 is altered throughout the course of disease progression in mice. Further studies in human ALS may validate the suitability of serum MMP-9 activity as a biomarker for early stage disease.
Publisher: Wiley
Date: 14-01-2017
DOI: 10.1111/AJD.12437
Abstract: Scalp melanoma has a worse prognosis than melanoma elsewhere, though the reasons for this are poorly understood. Current literature describing the clinicopathological associations of scalp melanoma is sparse. This study aims to compare clinical and histological features of scalp melanoma with other cutaneous head and neck melanomas (CHNM). A cross-sectional study was performed of all primary CHNM cases seen by the Victorian Melanoma Service between 1994 and 2014, using prospectively recorded clinical data. Invasive and in situ melanomas were compared separately. Invasive scalp melanoma was associated with male sex (OR, 2.7 95% CI, 1.9-3.9), increasing age (OR, 1.02 per year increase in age 95% CI, 1.01-1.03), being first noticed by a person other than self, spouse/relative or doctor (OR, 2.9 95% CI, 1.5-5.7), amelanosis (OR, 1.6 95% CI, 1.1-2.3), and increased growth rate (OR, 1.14 per 1 mm/month growth rate increase 95% CI, 1.04-1.26). Compared with other CHNM, scalp melanoma had greater median Breslow thickness (2.8 vs 1.2 mm) and was independently associated with satellite metastases (OR, 4.7 95% CI, 1.9-11.5) and nodular subtype (OR, 1.8 95% CI, 1.1-3.1). In situ scalp melanoma was associated with male sex, increasing age and solar keratoses. Scalp melanoma tends to occur in older men, is often rapidly growing and amelanotic, and is associated with high risk histological features. As it is likely to be overlooked, increased recognition of the atypical presentations of scalp melanoma is required.
Publisher: Elsevier BV
Date: 06-2000
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.FREERADBIOMED.2014.01.041
Abstract: Traumatic brain injury (TBI) is in part complicated by pro-oxidant iron elevation independent of brain hemorrhage. Ceruloplasmin (CP) and β-amyloid protein precursor (APP) are known neuroprotective proteins that reduce oxidative damage through iron regulation. We surveyed iron, CP, and APP in brain tissue from control and TBI-affected patients who were stratified according to time of death following injury. We observed CP and APP induction after TBI accompanying iron accumulation. Elevated APP and CP expression was also observed in a mouse model of focal cortical contusion injury concomitant with iron elevation. To determine if changes in APP or CP were neuroprotective we employed the same TBI model on APP(-/-) and CP(-/-) mice and found that both exhibited exaggerated infarct volume and iron accumulation postinjury. Evidence supports a regulatory role of both proteins in defence against iron-induced oxidative damage after TBI, which presents as a tractable therapeutic target.
Publisher: Springer Science and Business Media LLC
Date: 27-11-2012
DOI: 10.1038/BJC.2012.531
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2014
Publisher: Oxford University Press (OUP)
Date: 08-2013
DOI: 10.1111/BJD.12376
Abstract: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with a high mortality rate. Diagnosis is often delayed. To characterize the dermoscopic features of MCC. Clinical and dermoscopic images of 12 biopsy-proven MCCs were analysed in a retrospective manner, with existing dermoscopic criteria being scored independently by three dermatologists. The four most frequent clinical features were cherry red colour, shiny surface, sharp circumscription and nodular morphology. Significant dermoscopic features included linear irregular and polymorphous vessels, poorly focused vessels, milky pink areas, white areas, structureless areas and architectural disorder. Pigmented structures were absent from all lesions. The dermoscopic features described herein help the clinician to distinguish MCC from other benign and malignant red nodules. Increasing recognition of the presenting features will facilitate earlier diagnosis of MCC and reduced mortality.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2018
Publisher: Elsevier BV
Date: 03-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-10-2008
Publisher: Springer Science and Business Media LLC
Date: 17-12-2016
DOI: 10.1038/BJC.2015.437
Publisher: Wiley
Date: 10-2009
DOI: 10.1111/J.1365-2559.2009.03407.X
Abstract: There has been much debate about the existence of juvenile polymyositis (JPM) as an entity distinct from muscular dystrophy (MD). The aim of this study was to retrospectively analyse muscle biopsies and clinical features of 13 Australian children given an initial diagnosis of JPM, to determine their clinicopathological, immunohistochemical and molecular characteristics. The muscle biopsies on 13 cases were reviewed using detailed morphological and immunoperoxidase studies, with additional protein and molecular analyses, in conjunction with clinical review. Only one case had a true connective tissue disease inflammatory myopathy. Twelve (92.3%) cases with an initial diagnosis of JPM were found on clinical, pathological and molecular review to be MD. Inflammatory changes in apparently sporadic juvenile myopathies should prompt consideration of an early presentation of MD. Detailed analysis of muscle histopathology, specifically the detection of subsarcolemmal blebbing, isolated fibre degeneration occurring independent of inflammatory infiltrates, patchy clustered major histocompatibility complex-I expression and a CD68+/CD3+ perimysial infiltrate, assists in the diagnosis of early MD. Specific protein and gene analysis adds support to the pathological diagnosis of dystrophy. This series adds weight to suggestions that JPM may not represent a discrete clinical or pathological entity.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.HEALUN.2010.02.009
Abstract: This study was conducted in donor hearts obtained after cardiocirculatory death (DCD) to determine whether pre-reperfusion cardioplegia, followed by warm blood perfusion, is superior to cold storage in preserving function sufficient for transplantation. Greyhound dogs (n = 15) were anesthetized and cardiocirculatory death and circulatory failure was induced by cessation of mechanical ventilation. After 30-minutes, the hearts were preserved by perfusion or were infused with modified St. Thomas' cardioplegia, explanted, and stored for 4 hour at 4 degrees C. Perfusion hearts were briefly reperfused with an acidic, mitochondrial protective cardioplegic solution and then continuously perfused for 4 hours with normothermic blood. Hearts from a normal reference group (no cardiocirculatory arrest) were preserved by St. Thomas' cardioplegia and cold storage. In all groups, 40 minutes of room temperature ischemia was used to simulate the conditions of transplantation. Final functional and metabolic assessments were made on a working heart apparatus. Perfusion hearts (n = 6), when compared with cold storage hearts (n = 6), produced a greater rate of change in left ventricular pressure (1121 +/- 273 vs 336 +/- 193 mm Hg/sec, p = 0.04), greater echocardiographic fractional area reduction (71.3% +/- 10.0% vs 25.4% +/- 2.9% of baseline, p = 0.004) and lower perfusate lactate levels (1.5 +/- 1.4 vs 9.7 +/- 1.4 mmol/liter p = 0.002). Functional recovery in perfusion hearts was comparable to the normal hearts (n = 3). For DCD hearts, a strategy of pre-reperfusion cardioplegia, followed by continuous warm blood perfusion, is superior to cold storage. These results suggest DCD hearts may be more suitable for transplantation after continuous warm blood perfusion than after cold storage.
Publisher: Elsevier BV
Date: 06-2009
Abstract: Despite the development of targeted therapies for pulmonary arterial hypertension (PAH), some patients fail to respond to medical therapy. There are a number of types of PAH, one of which is pulmonary venoocclusive disease (PVOD). Unlike other PAH types, the hallmark pathology of PVOD is fibrous occlusion of the small venules, potentially with arterial involvement. It was hypothesized that a lack of response to medical therapy in clinically diagnosed PAH can be explained by misdiagnosed PVOD. This study reviewed cases of 14 patients with clinically diagnosed PAH who had failed to respond to medical therapy and had lung tissue available from autopsy or explant. Control s les (n = 6) were obtained from lungs explanted for other causes, and a previous transthoracic echocardiogram excluded pulmonary hypertension. Comprehensive vessel morphometry was performed, and the clinical data reviewed. Vessel analysis confirmed 86% of case patients had PVOD and 14% had arterial-only PAH (artPAH). In the PVOD case patients, significant pathology was present in all vessel types with similar obstructive, intimal fibrosis in the venules (p < 0.0001) and arterioles (p < 0.0001). This was considerably different from the intimal concentric laminar smooth muscle proliferation in the artPAH cases. There were no significant differences in clinical presentation between PVOD and artPAH case patients. Pulmonary edema was not observed in the PVOD cases. PVOD is an underdiagnosed and commonly misdiagnosed cause of pulmonary hypertension, which may present with a failure to respond to medical therapy. Further studies on PVOD may help confirm whether a change in its classification as a type of PAH is necessary.
Publisher: Royal College of Psychiatrists
Date: 04-2009
DOI: 10.1192/BJP.BP.108.057034
Abstract: Few studies have investigated the relationship between schizophrenia and frontotemporal dementia. To investigate this relationship through a clinicopathological investigation of young-onset frontotemporal dementia and a review of the case literature. Cases of young-onset frontotemporal dementia were identified within the local brain bank. The clinical course and pathological findings were collated. For the literature review, cases of frontotemporal dementia identified through Medline were selected according to defined criteria. The demographic, clinical, pathological and genetic characteristics of cases presenting with a psychotic illness were identified. In the case series, 5 of 17 patients with frontotemporal dementia had presented with a psychotic illness (schizophrenia/schizoaffective disorder n =4, bipolar disorder n =1) an average of 5 years prior to the dementia diagnosis. Patients with schizophrenia exhibited changes consistent with TDP-43 and ubiquitin-positive frontotemporal dementia. In the cases review, a third of patients aged 30 years or under and a quarter of those aged 40 years or under had been diagnosed with psychosis at presentation. Patients with young-onset frontotemporal dementia may be diagnosed with a psychotic illness years before the dementia diagnosis is made. These findings have implications for clinicians and for our further understanding of the neurobiology of psychotic illness.
Publisher: Wiley
Date: 09-2011
DOI: 10.1111/J.1749-6632.2011.06158.X
Abstract: The association of bilateral vestibulopathy with cerebellar ataxia was first reported in 1991 and delineated as a distinct syndrome with a characteristic and measurable clinical sign--an absent visually enhanced vestibulo-ocular reflex--in 2004. We reviewed 27 patients with this syndrome and show that a non-length-dependent sensory deficit with absent sensory nerve action potentials is an integral component of this syndrome, which we now call "cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome" (CANVAS). All patients had brain MRI and 22/27 had evidence of cerebellar atrophy involving anterior and dorsal vermis, as well as the hemispheric crus I. Brain and temporal bone pathology in one patient showed marked loss of Purkinje cells and of vestibular, trigeminal, and facial ganglion cells, but not of spiral ganglion cells. There are two sets of sibling pairs, suggesting CANVAS is a late-onset recessive disorder. The characteristic clinical sign-the visual vestibulo-ocular reflex deficit-can be demonstrated and measured clinically using video-oculography.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2014
DOI: 10.1007/S10549-014-3209-Y
Abstract: Aberrant DNA methylation is a key feature of breast carcinoma. We aimed to test the association between breast cancer risk and epigenome-wide methylation in DNA from peripheral blood. Nested case-control study within the prospective Melbourne Collaborative Cohort Study. DNA was extracted from before-diagnosis blood s les (420 incident cases and matched controls). Methylation was measured with the Illumina Infinium Human Methylation 450 BeadChip array. Odds ratio (OR) for epigenome-wide methylation, quantified as the mean beta values across the CpGs, in relation to breast cancer risk were estimated using conditional logistic regression. Overall, the OR for breast cancer was 0.42 (95% CI 0.20-0.90) for the top versus bottom quartile of epigenome-wide DNA methylation and the OR for a one standard deviation increment was 0.69 (95% CI 0.50-0.95 test for linear trend, p = 0.02). Epigenome-wide DNA methylation of CpGs within functional promoters was associated with an increased risk, whereas epigenome-wide DNA methylation of genomic regions outside promoters was associated with decreased risk (test for heterogeneity, p = 0.0002). The increased risk associated with epigenome-wide DNA methylation in functional promoters did not vary by time between blood collection and diagnosis, whereas the inverse association with epigenome-wide DNA methylation outside functional promoters was strongest when the interval from blood collection to diagnosis was less than 5 years and weakest for the longest interval. Epigenome-wide methylation in DNA extracted from peripheral blood collected before diagnosis may have potential utility as markers of breast cancer risk and for early detection.
Publisher: Elsevier BV
Date: 09-1997
DOI: 10.1016/S0140-6736(97)24039-0
Abstract: When compared to adipocytes in other anatomical sites, the interaction of bone marrow resident adipocytes with the other cells in their microenvironment is less well understood. Bone marrow adipocytes originate from a resident, self-renewing population of multipotent bone marrow stromal cells which can also give rise to other lineages such as osteoblasts. The differentiation fate of these mesenchymal progenitors can be influenced to favour adipogenesis by several factors, including the administration of thiazolidinediones and increased age. Experimental data suggests that increases in bone marrow adipose tissue volume may make bone both more attractive to metastasis and conducive to cancer cell growth. Bone marrow adipocytes are known to secrete a variety of lipids, cytokines and bioactive signaling molecules known as adipokines, which have been implicated as mediators of the interaction between adipocytes and cancer cells. Recent studies have provided new insight into the impact of bone marrow adipose tissue volume expansion in regard to supporting and exacerbating the effects of bone metastasis from solid tumors, focusing on prostate, breast and lung cancer and blood cancers, focusing on multiple myeloma. In this mini-review, recent research developments pertaining to the role of factors which increase bone marrow adipose tissue volume, as well as the role of adipocyte secreted factors, in the progression of bone metastatic prostate and breast cancer are assessed. In particular, recent findings regarding the complex cross-talk between adipocytes and metastatic cells of both lung and prostate cancer are highlighted.
Publisher: Elsevier BV
Date: 1989
DOI: 10.3109/00313028909061074
Abstract: Current biological concepts of borderline personality disorder (BPD) emphasize the interference of emotional hyperarousal and cognitive functions. A prototypical ex le is episodic memory. Pre-clinical investigations of emotion-episodic memory interactions have shown specific retrograde and anterograde episodic memory changes in response to emotional stimuli. These changes are amygdala dependent and vary as a function of emotional arousal and valence. To determine whether there is amygdala hyper-responsiveness to emotional stimuli as the underlying pathological substrate of cognitive dysfunction in BPD, 16 unmedicated female patients with BPD were tested on the behavioural indices of emotion-induced amnesia and hypermnesia established in 16 healthy controls. BPD patients displayed enhanced retrograde and anterograde amnesia in response to presentation of negative stimuli, while positive stimuli elicited no episodic memory-modulating effects. These findings suggest that an amygdala hyper-responsiveness to negative stimuli may serve as a crucial aetiological contributor to emotion-induced cognitive dysfunction in BPD.
Publisher: Wiley
Date: 04-2014
DOI: 10.1111/BPA.12104
Publisher: BMJ
Date: 06-02-2013
Publisher: Society for Neuroscience
Date: 05-2017
DOI: 10.1523/ENEURO.0142-17.2017
Abstract: Axonal damage and demyelination are major determinants of disability in patients with peripheral demyelinating neuropathies. The neurotrophin family of growth factors are essential for the normal development and myelination of the peripheral nervous system (PNS), and as such are potential therapeutic candidates for ameliorating axonal and myelin damage. In particular, BDNF promotes peripheral nerve myelination via p75 neurotrophin receptor (p75 NTR ) receptors. Here, we investigated the therapeutic efficacy of a small structural mimetic of the region of BDNF that binds to p75 NTR (cyclo- d PAKKR) in experimental autoimmune neuritis (EAN), an established animal model of peripheral demyelinating neuropathy. Examination of rodents induced with EAN revealed that p75 NTR is abundantly expressed in affected peripheral nerves. We found that systemic administration of cyclo- d PAKKR ameliorates EAN disease severity and accelerates recovery. Animals treated with cyclo- d PAKKR displayed significantly better motor performance compared to control animals. Histological assessment revealed that cyclo- d PAKKR administration limits the extent of inflammatory demyelination and axonal damage, and protects against the disruption of nodal architecture in affected peripheral nerves. In contrast, a structural control peptide of cyclo- d PAKKR exerted no influence. Moreover, all the beneficial effects of cyclo- d PAKKR in EAN are abrogated in p75 NTR heterozygous mice, strongly suggesting a p75 NTR -dependent effect. Taken together, our data demonstrate that cyclo- d PAKKR ameliorates functional and pathological defects of EAN in a p75 NTR -dependant manner, suggesting that p75 NTR is a therapeutic target to consider for future treatment of peripheral demyelinating diseases and targeting of p75 NTR is a strategy worthy of further investigation.
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: Wiley
Date: 17-08-2011
DOI: 10.1111/J.1463-1318.2011.02673.X
Abstract: The study aimed to assess whether the ex vivo injection of patent blue V dye would increase lymph node yield in operative specimens of colorectal cancer. A randomized controlled trial was carried out in which patients undergoing resection for colonic cancer were allocated to patent V blue or no patent blue V dye submucosal injection of the operative specimen. The number of lymph nodes found in each group was compared. Between 1 January and 31 December 2008, 68 patients were randomized. Thirty-three patients received patent blue V dye and 34 did not. In the former group the median number of blue nodes identified was 11, compared with a median of 9 in the no dye group. After the application of Carnoy's solution lymph node count was 16 in each group. There was no significant difference between all these results. Ex vivo injection of patent blue V dye submucosally in a peritumour location did not increase the lymph node count or the percentage of specimens having more than 12 lymph nodes identified.
Publisher: Elsevier BV
Date: 08-2009
Publisher: Wiley
Date: 13-06-2006
DOI: 10.1111/J.1445-5994.2006.01103.X
Abstract: Patients with interstitial lung disease (ILD) very frequently die before the opportunity to receive lung transplantation (LTx). This retrospective study describes the clinical course of 86 patients with ILD referred for LTx assessment between January 1999 and December 2002. (i) To describe the outcomes, (ii) to identify reasons of delay to transplantation, (iii) to describe the causes of death/complications and (iv) to assess the pathological diagnosis and concordance with explanted lung pathology. Data were collected from the case notes of all patients with ILD referred to the Alfred Hospital over a 4-year period. Twenty women and 66 men, mean age of 55 +/- 8 years, were referred for LTx assessment. Forty-five patients were deemed not suitable for LTx and 41 were listed. Twenty-two patients underwent transplantation, 16 died on the waiting list and 7 are still on the waiting list. Complications were frequent (e.g. pulmonary embolism, malignancy and infection) and carried high mortality. Patients dying on the waiting list appeared generally to be in accelerated decline, dying shortly after listing, with no evidence in their lung function test assessment predicting them as a poor prognosis group. Serious complications and death on the waiting list of patients with idiopathic pulmonary fibrosis are high, not apparently because of delayed referral but usually in patients undergoing very rapid decline.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-09-2013
Publisher: Elsevier BV
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 14-08-2013
DOI: 10.1007/S00270-013-0704-1
Abstract: Electroporation-based therapies deliver brief electric pulses into a targeted volume to destabilize cellular membranes. Nonthermal irreversible electroporation (IRE) provides focal ablation with effects dependent on the electric field distribution, which changes in heterogeneous environments. It should be determined if highly conductive metallic implants in targeted regions, such as radiotherapy brachytherapy seeds in prostate tissue, will alter treatment outcomes. Theoretical and experimental models determine the impact of prostate brachytherapy seeds on IRE treatments. This study delivered IRE pulses in nonanimal, as well as in ex vivo and in vivo tissue, with and in the absence of expired radiotherapy seeds. Electrical current was measured and lesion dimensions were examined macroscopically and with magnetic resonance imaging. Finite-element treatment simulations predicted the effects of brachytherapy seeds in the targeted region on electrical current, electric field, and temperature distributions. There was no significant difference in electrical behavior in tissue containing a grid of expired radiotherapy seeds relative to those without seeds for nonanimal, ex vivo, and in vivo experiments (all p > 0.1). Numerical simulations predict no significant alteration of electric field or thermal effects (all p > 0.1). Histology showed cellular necrosis in the region near the electrodes and seeds within the ablation region however, there were no seeds beyond the ablation margins. This study suggests that electroporation therapies can be implemented in regions containing small metallic implants without significant changes to electrical and thermal effects relative to use in tissue without the implants. This supports the ability to use IRE as a salvage therapy option for brachytherapy.
Publisher: Elsevier BV
Date: 06-2011
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2022
DOI: 10.1161/STROKEAHA.121.038364
Abstract: Recent reports raise the possibility of cerebral amyloid angiopathy (CAA) leading to intracerebral hemorrhage in young adults following childhood neurosurgery, suggesting transmission of amyloid-β (Aβ) through neurosurgical procedures including dura mater grafting. Parenchymal Aβ deposition, and to a lesser extent tau aggregation, similar to that seen in Alzheimer disease, have also been described. We conducted a database review of 634 consecutive intracerebral hemorrhage patients aged years at a tertiary stroke center over 20 years to identify such patients. We identified 3 patients aged in their thirties who presented with spontaneous lobar intracerebral hemorrhage, with imaging or neuropathology consistent with CAA, and a history of childhood neurosurgery. Two of these patients had undergone a dural repair using cadaveric dura mater (Lyodura). In addition to CAA, both patients had neuropathologically confirmed parenchymal Aβ and tau deposits, characteristic of Alzheimer disease. Our findings support the concept of neurosurgical Aβ transmission but suggest that such cases are rare in standard clinical practice.
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.JID.2019.07.725
Abstract: Lentigo maligna (LM) is a common subtype of in situ melanoma on chronically sun-exposed skin, particularly the head and neck of older patients. Although surgery is the standard treatment, there is associated morbidity, and options such as imiquimod cream or radiotherapy may be used if surgery is refused or inappropriate. Complete response rates following imiquimod treatment are variable in the literature. The aim of this study was to evaluate the host immune response both before and following treatment with imiquimod to better identify likely responders. Paired pre- and post-imiquimod treatment specimens were available for 27 patients. Patients were treated with imiquimod 5 days per week for 12 weeks at 16 weeks, lesions were excised for histological assessment. Of the 27 patients, 16 were responders and 11 failed to clear the disease. PDL1 protein expression was increased, accompanied by a unique gene signature in lesions from patients that subsequently histologically cleared LM by 16 weeks. This comprised 57 upregulated immune genes in signaling networks for antigen presentation, type I interferon signaling, and T-cell activation. This may represent an early responder group to imiquimod, and this unique gene signature potentially can be used as a biomarker of LM response to imiquimod.
Publisher: MDPI AG
Date: 25-11-2022
Abstract: Current therapeutics targeting chronic phases of multiple sclerosis (MS) are considerably limited in reversing the neural damage resulting from repeated inflammation and demyelination insults in the multi-focal lesions. This inflammation is propagated by the activation of microglia, the endogenous immune cell aiding in the central nervous system homeostasis. Activated microglia may transition into polarized phenotypes namely, the classically activated proinflammatory phenotype (previously categorized as M1) and the alternatively activated anti-inflammatory phenotype (previously, M2). These transitional microglial phenotypes are dynamic states, existing as a continuum. Shifting microglial polarization to an anti-inflammatory status may be a potential therapeutic strategy that can be harnessed to limit neuroinflammation and further neurodegeneration in MS. Our research has observed that the obstruction of signaling by inhibitory myelin proteins such as myelin-associated inhibitory factor, Nogo-A, with its receptor (NgR), can regulate microglial cell function and activity in pre-clinical animal studies. Our review explores the microglial role and polarization in MS pathology. Additionally, the potential therapeutics of targeting Nogo-A/NgR cellular mechanisms on microglia migration, polarization and phagocytosis for neurorepair in MS and other demyelination diseases will be discussed.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-04-2022
DOI: 10.1126/SCITRANSLMED.AAZ8454
Abstract: Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood s les collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3 + CD4 + T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1β and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.
Publisher: Oxford University Press (OUP)
Date: 07-06-2017
DOI: 10.1093/JNEN/NLX041
Publisher: Springer Science and Business Media LLC
Date: 19-10-2019
DOI: 10.1007/S00381-018-3988-2
Abstract: Intracranial epithelioid haemangioendothelioma (EHE) is a rare intermediate grade vascular tumour with heterogeneous clinical and histopathological behaviour. We present the surgical considerations of an exceptionally large skull-based EHE in an 11-year old female who presented to our institution with headaches and a protuberance over the left parietal area. Magnetic resonance imaging (MRI) demonstrated a left sided 10.5 × 6.6 × 11.1 cm extra-axial tumour arising from the parieto-temporaloccipital region which was continuous with the calvarium. An initial biopsy confirmed EHE. Staged treatment involved preoperative angiography and embolization. The patient underwent an extensive tumour excision and acrylic cranioplasty. Residual tumour persists in the petrous temporal bone. No neurological deficit was sustained. Postoperatively, we proceeded to tumour surveillance rather than adjuvant therapies, and follow-up imaging up to 36 months postoperatively has shown no tumour progression. We illustrate our surgical management of this large EHE and review the literature of this rare pathological entity with variable tumour behaviour and potential role for adjuvant therapy.
Publisher: Springer Science and Business Media LLC
Date: 04-01-2014
DOI: 10.1245/S10434-013-3448-X
Abstract: Fine-needle aspiration cytology (FNAC) assists the diagnosis of thyroid malignancy. A 'suspicious for malignancy' on FNAC creates a management dilemma. The aims of this study were to investigate the malignancy rate for patients with suspicious cytology, and to describe a management approach for those with a suspicious result. A retrospective review of prospectively collected data in an endocrine surgery database was undertaken. Patients undergoing thyroidectomy with preoperative FNAC from 1992 to 2012 were analysed. Preoperative FNAC was undertaken in 2,692 patients, and the FNAC result was 'suspicious for malignancy' in 94 (3.5 %) patients. Of these, 53 (56.4 %) were malignant, with the majority 44 (83.0 %) being papillary thyroid cancer. 48 patients went straight to total thyroidectomy, 40 patients had an initial diagnostic hemithyroidectomy, and 1 patient had a diagnostic isthmusectomy. 5 patients required reoperative total thyroidectomy as an initial procedure. Of the 94 suspicious cases, 55 were reported by an unknown, presumably non-expert, thyroid cytopathologist. 38 of these cases were available for review and re-reporting by an experienced cytopathologist. On review, 28 (73.7 %) were reclassified as cytologically malignant, and all of these were confirmed as malignant on subsequent histopathology. Suspicious cytology has a high risk of malignancy. Expert thyroid cytopathology can improve diagnostic accuracy and a preoperative malignant diagnosis should be pursued to enable one-stage surgery where possible.
Publisher: Wiley
Date: 04-1999
DOI: 10.1046/J.1471-4159.1999.721600.X
Abstract: The glycosylation of acetylcholinesterase (AChE) in CSF was analyzed by lectin binding. AChE from Alzheimer's disease (AD) patients was found to bind differently to two lectins, concanavalin A and wheat germ agglutinin, than AChE from controls. As multiple isoforms of AChE are present in both CSF and brain, we examined whether the abnormal glycosylation of AD AChE was due to changes in a specific molecular isoform. Globular hiphilic dimeric (G2a) and monomeric (G1a) isoforms of AChE were found to be differentially glycosylated in AD CSF. Glycosylation of AChE was also altered in AD frontal cortex but not in cerebellum and was also associated with an increase in the proportion of light (G2 and G1) isoforms. This study demonstrates that the glycosylation of AChE is altered in the AD brain and that changes in AChE glycosylation in AD CSF may reflect changes in the distribution of brain isoforms. The study also suggests that glycosylation of AChE may be a useful diagnostic marker for AD.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2002
DOI: 10.1007/S00401-002-0529-5
Abstract: The aim of this study was to assess the variation between neuropathologists in the diagnosis of common dementia syndromes when multiple published protocols are applied. Fourteen out of 18 Australian neuropathologists participated in diagnosing 20 cases (16 cases of dementia, 4 age-matched controls) using consensus diagnostic methods. Diagnostic criteria, clinical synopses and slides from multiple brain regions were sent to participants who were asked for case diagnoses. Diagnostic sensitivity, specificity, predictive value, accuracy and variability were determined using percentage agreement and kappa statistics. Using CERAD criteria, there was a high inter-rater agreement for cases with probable and definite Alzheimer's disease but low agreement for cases with possible Alzheimer's disease. Braak staging and the application of criteria for dementia with Lewy bodies also resulted in high inter-rater agreement. There was poor agreement for the diagnosis of frontotemporal dementia and for identifying small vessel disease. Participants rarely diagnosed more than one disease in any case. To improve efficiency when applying multiple diagnostic criteria, several simplifications were proposed and tested on 5 of the original 20 cases. Inter-rater reliability for the diagnosis of Alzheimer's disease and dementia with Lewy bodies significantly improved. Further development of simple and accurate methods to identify small vessel lesions and diagnose frontotemporal dementia is warranted.
Publisher: Wiley
Date: 22-02-2018
DOI: 10.1111/ANS.13446
Publisher: Wiley
Date: 10-1999
DOI: 10.1046/J.1471-4159.1999.0731557.X
Abstract: The neurodegeneration seen in spongiform encephalopathies is believed to be mediated by protease-resistant forms of the prion protein (PrP). A peptide encompassing residues 106-126 of human PrP has been shown to be neurotoxic in vitro. The neurotoxicity of PrP106-126 appears to be dependent upon its adoption of an aggregated fibril structure. To examine the role of the hydrophobic core, AGAAAAGA, on PrP106-126 toxicity, we performed structure-activity analyses by substituting two or more hydrophobic residues for the hydrophilic serine residue to decrease its hydrophobicity. A peptide with a deleted alanine was also synthesized. We found all the peptides except the deletion mutant were no longer toxic on mouse cerebellar neuronal cultures. Circular dichroism analysis showed that the nontoxic PrP peptides had a marked decrease in beta-sheet structure. In addition, the mutants had alterations in aggregability as measured by turbidity, Congo red binding, and fibril staining using electron microscopy. These data show that the hydrophobic core sequence is important for PrP106-126 toxicity probably by influencing its assembly into a neurotoxic structure. The hydrophobic sequence may similarly affect aggregation and toxicity observed in prion diseases.
Publisher: Springer Science and Business Media LLC
Date: 15-09-2016
DOI: 10.1007/S00125-016-4084-3
Abstract: In obesity oxidative stress is thought to contribute to the development of insulin resistance, non-alcoholic fatty liver disease and the progression to non-alcoholic steatohepatitis. Our aim was to examine the precise contributions of hepatocyte-derived H Glutathione peroxidase (GPX) 1 is an antioxidant enzyme that is abundant in the liver and converts H Chow-fed Alb-Cre Gpx1 Increased hepatocyte-derived H
Publisher: Oxford University Press (OUP)
Date: 2014
DOI: 10.1039/C4MT00060A
Abstract: Serum zinc decreases with age.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier BV
Date: 10-2009
Publisher: Oxford University Press (OUP)
Date: 2015
DOI: 10.1039/C4MT00258J
Abstract: Following acute brain injury ( hours post-event), cobalt levels in the brain are significantly elevated. This elevation may have important implications for positron emission tomography neuroimaging for assessing brain injury severity.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Wiley
Date: 12-11-2016
DOI: 10.1111/AJD.12416
Abstract: Missed opportunities in the diagnosis of nodular melanoma (NM) carry high prognostic penalties due to the rapid rate of NM growth. To date, an assessment of the pathways to diagnosis of NM versus superficial spreading melanoma (SSM) specifically comparing numbers of opportunities missed to undertake biopsy has not been performed. A retrospective questionnaire of 120 patients (60 NM patients, age and sex matched to 60 SSM patients) from the Victorian Melanoma Service (VMS) database was undertaken to assess pathways to diagnosis. The numbers of opportunities missed to undertake a biopsy and doctor behaviour at such encounters were recorded. Diagnostic delay (overall, patient's and doctor's delay) in terms of time was assessed. Significant differences in opportunities missed to make a diagnosis of NM compared to SSM were found. In all, 43% of NM were biopsied at a first encounter compared to 70% of SSM. All SSM were diagnosed within three reviews. Overall, 33% of NM required at least three and up six reviews until biopsy. Patients with NM were more likely than those with SSM to be reassured that their lesions were benign. No significant differences in terms of time delay to diagnosis between NM and SSM were found. NM contributes disproportionately to melanoma mortality in Australia. Addressing earlier diagnosis of NM with renewed focus may make the biggest impact on the overall mortality of melanoma. The message that a period of observation is not appropriate for patients re-presenting with lesions of concern must be more effectively communicated.
Publisher: Wiley
Date: 29-06-2018
DOI: 10.1111/AJD.12659
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.PATHOL.2021.11.002
Abstract: Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF
Publisher: Oxford University Press (OUP)
Date: 19-05-2011
DOI: 10.1093/HMG/DDR228
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.JHEP.2005.01.031
Abstract: Chronic hepatitis B (CHB) and C (CHC) are commonly associated with hepatic steatosis. The aims of this study were to investigate predictors of hepatic steatosis, and their impact on inflammation and fibrosis in CHB and CHC. Consecutive patients with either CHB or CHC who underwent a liver biopsy at The Alfred Hospital between April and September 2002 were included. Histological analysis of liver biopsies was performed by two hepatopathologists blinded to the clinical data. Ninety-one patients were analysed including 17 patients with CHB and 74 with CHC. CHC genotype 3, C-peptide, glucose and waist circumference were independent predictors of extent of Brunt steatosis grade, while CHC genotype 3, C-peptide and waist circumference were independent predictors of microvesicular steatosis grade. Alcohol intake and age were predictors of hepatic fibrosis. There was a trend toward a correlation between both Brunt steatosis and microvesicular steatosis grades and fibrosis progression rate in CHC genotype non-3. Hepatic steatosis is common in chronic hepatitis B and C, and is associated with waist circumference, glucose, C-peptide and chronic hepatitis C genotype 3. Steatosis grade appears to relate to hepatic fibrosis progression rate in chronic hepatitis C genotype non-3.
Publisher: Oxford University Press (OUP)
Date: 21-06-2018
DOI: 10.1111/BJD.16556
Publisher: Wiley
Date: 12-11-2015
DOI: 10.1111/AJD.12413
Abstract: Australia has the highest incidence and mortality rates for melanoma in the world. The Victorian Melanoma Service began operation in 1994 as one of the first multidisciplinary melanoma clinics in Victoria. We conducted a review of the Victorian Melanoma Service database of 6721 patients and present the trends observed in a statewide referral centre in Australia. Our results highlight the importance of multidisciplinary care of melanoma patients and emphasise the significance of histological reviews and dermatological skin assessments for the detection of synchronous melanoma.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.NUCMEDBIO.2012.03.001
Abstract: Amyloid-β (Aβ) plaques are a major pathological hallmark of Alzheimer's disease (AD). The noninvasive detection of Aβ plaques may increase the accuracy of clinical diagnosis as well as monitor therapeutic interventions. While [(11)C]-PiB is the most widely used Aβ positron emission tomography (PET) radiotracer, due to the short half-life of (11)C (20 min), its application is limited to centers with an on-site cyclotron and (11)C radiochemistry expertise. Therefore, novel [(18)F] (half-life 110 min)-labeled Aβ PET tracers have been developed. We have demonstrated that [(18)F]-florbetaben-PET can differentiate in iduals diagnosed with AD from healthy elderly, Parkinson's disease and frontotemporal lobe dementia (FTLD-tau) patients. While [(18)F]-florbetaben-PET retention matched the reported postmortem distribution of Aβ plaques, the nature of [(18)F]-florbetaben binding to other pathological lesions comprising misfolded proteins needs further assessment. The objective of this study was to determine whether Florbetaben selectively binds to Aβ plaques in postmortem tissue specimens containing mixed pathological hallmarks (i.e., tau and α-synuclein aggregates). Human AD, FTLD-tau and dementia with Lewy bodies (DLB) brain sections were analyzed by [(18)F]-florbetaben autoradiography and [(3)H]-florbetaben high-resolution emulsion autoradiography and [(19)F]-florbetaben fluorescence microscopy. Both autoradiographical analyses demonstrated that Florbetaben exclusively bound Aβ plaques in AD brain sections at low nanomolar concentrations. Furthermore, at concentrations thousand-folds higher than those during a PET scan, [(19)F]-florbetaben did not bind to α-synuclein or tau aggregates in DLB and FTLD-tau brain sections, respectively. Detection of [(19)F]-florbetaben staining by fluorescence microscopy in several AD brain regions demonstrated that Florbetaben identified Aβ plaques in all brain regions examined. This study provides further evidence that [(18)F]-florbetaben-PET is a highly selective radiotracer to assess Aβ plaque deposition in the brain.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Society of Nuclear Medicine
Date: 21-01-2009
DOI: 10.2967/JNUMED.108.057984
Abstract: 11C-Pittsburgh Compound B (11C-PiB) PET has demonstrated significantly higher PiB retention in the gray matter of Alzheimer disease (AD) patients than in healthy controls (HCs). PiB is similarly retained within the white matter of HC and AD brains. Although the specificity of PiB for Abeta plaques in gray matter has been well described, the nature of PiB binding to white matter remains unclear. In this study, we characterized the binding of PiB to human white matter homogenates. In vitro binding studies were conducted using 3H-PiB (0.1-500 nM) and white matter brain homogenates (100 microg) from 3 AD patients and 3 HCs. Nonspecific binding was determined using PiB (1 microM). White matter from the same patients was also analyzed by immunofluorescence/immunohistochemistry (IF/IHC) microscopy and Western blotting for Abeta expression. White matter kinetics were also characterized in vivo through 11C-PiB PET studies in 27 HCs and 34 patients with dementia. IF/IHC experiments were conducted on 1 postmortem patient with dementia, to compare with the 11C-PiB distribution volume ratio data acquired 23 mo earlier. In vitro saturation studies indicated that 3H-PiB binds nonspecifically to white matter brain homogenates. PiB fluorescence staining of AD and HC brain sections was consistent with absence of Abeta in IHC staining. Higher gray matter-to-white matter ratios were observed in IHC images than in 11C-PiB PET images. These studies suggest that PiB binding to white matter is mainly nonsaturable and nonspecific and that PiB retention in the 11C-PiB PET studies is largely attributable to slower PiB white matter kinetics.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.NMD.2010.05.012
Abstract: We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirming the importance of this causal association. The p.R168C TPM3 mutation we identified has been reported in two previous patients. The histological changes associated with this mutation vary widely from typical cap myopathy with near complete type 1 predominance (two patients), to typical congenital fibre-type disproportion without protein inclusions (one patient). We performed 2D-gel electrophoresis using muscle biopsies from two patients with the p.R168C mutation and show that mutant protein accounts for around 50% of alpha-tropomyosin(slow) in sarcomeres, consistent with a dominant negative mechanism of disease pathogenesis.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 02-2015
Publisher: Wiley
Date: 08-1991
DOI: 10.1111/J.1365-2559.1991.TB00009.X
Abstract: An endocrine cell carcinoma in the gallbladder of a 59-year-old woman is reported. The morphological features of this diagnosis are compared with 14 previously reported primary gallbladder carcinoid tumours that had metastasized. The histogenesis and current classification of endocrine cell tumours is discussed.
Publisher: Springer Science and Business Media LLC
Date: 30-01-2018
DOI: 10.1038/S41366-018-0007-3
Abstract: In obese in iduals, nonalcoholic fatty liver disease (NAFLD) is common but often goes undiagnosed, and therefore untreated. The presence of significant fibrosis is a key determinant of NAFLD progression, and liver steatosis has substantial cardiovascular implications. We aimed to determine the diagnostic accuracy of common noninvasive diagnostic tests for steatosis and fibrosis in the obese. We recruited 182 severely and morbidly obese in iduals undergoing bariatric surgery (age 44 ± 12 years, body mass index 45.1 ± 8.3 kg/m
Publisher: Springer Science and Business Media LLC
Date: 29-01-2012
DOI: 10.1038/NM.2613
Abstract: The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically.
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.NBD.2005.11.010
Abstract: Apoptotic-like changes in the neocortex of control, pathologically aged and Alzheimer's disease (AD) cases were investigated. There was no increase in labeling or change in localization of labeling that distinguished between these cases for active caspase-3, -8, -9, Bax, Bcl-2 or TRADD. Bax, Bcl-2 and TRADD mRNA levels also differed little between case types, although there were small but significant decreases in Bax mRNA levels in AD compared to control cases and Bcl-2 mRNA in AD cases compared to pathologically aged and control cases. There was no difference in the percentage of apoptotic-like nuclei between these cases, except for a small but significant decrease in the inferior temporal gyrus of AD cases relative to controls. Nuclei observed within or adjacent to beta-amyloid plaques were rarely abnormal, and neurons bearing neurofibrillary tangles (NFTs) did not have abnormal nuclei. Apoptosis may not play a major role in the pathogenesis of neuronal degeneration of AD.
Publisher: Society for Neuroscience
Date: 26-09-2007
DOI: 10.1523/JNEUROSCI.0630-07.2007
Abstract: Dementia with Lewy bodies (DLB) is pathologically characterized by the presence of α-synuclein-containing Lewy bodies within the neocortical, limbic, and paralimbic regions. Like Alzheimer's disease (AD), Aβ plaques are also present in most DLB cases. The contribution of Aβ to the development of DLB is unclear. [ 11 C]-Pittsburgh compound B ([ 11 C]-PIB) is a thioflavin-T derivative that has allowed in vivo Aβ burden to be quantified using positron emission tomography (PET). [ 11 C]-PIB PET studies have shown similar high cortical [ 11 C]-PIB binding in AD and DLB subjects. To establish the potential binding of PIB to α-synuclein in DLB patients, we characterized the in vitro binding of PIB to recombinant human α-synuclein and DLB brain homogenates. Analysis of the in vitro binding studies indicated that [ 3 H]-PIB binds to α-synuclein fibrils but with lower affinity than that demonstrated/reported for Aβ 1–42 fibrils. Furthermore, [ 3 H]-PIB was observed to bind to Aβ plaque-containing DLB brain homogenates but failed to bind to DLB homogenates that were Aβ plaque-free (“pure DLB”). Positive PIB fluorescence staining of DLB brain sections colocalized with immunoreactive Aβ plaques but failed to stain Lewy bodies. Moreover, image quantification analysis suggested that given the small size and low density of Lewy bodies within the brains of DLB subjects, any contribution of Lewy bodies to the [ 11 C]-PIB PET signal would be negligible. These studies indicate that PIB retention observed within the cortical gray matter regions of DLB subjects in [ 11 C]-PIB PET studies is largely attributable to PIB binding to Aβ plaques and not Lewy bodies.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Frontiers Media SA
Date: 10-09-2018
Publisher: Wiley
Date: 06-03-2018
DOI: 10.1111/ANS.14407
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2011
Publisher: Oxford University Press (OUP)
Date: 24-03-2011
DOI: 10.1093/BRAIN/AWR038
Abstract: While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippoc al serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48% P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2010
Publisher: Springer Science and Business Media LLC
Date: 25-05-2021
DOI: 10.1038/S41467-021-23241-6
Abstract: INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P 2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA -mutant ER + breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA -mutant ER + breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P 2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER + breast cancer via PI(3,4)P 2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2017
Publisher: Oxford University Press (OUP)
Date: 02-2012
Publisher: Oxford University Press (OUP)
Date: 09-10-2017
DOI: 10.1093/IJE/DYX131
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-11-2016
DOI: 10.1126/SCITRANSLMED.AAF1629
Abstract: PAK4-CRTC1 signaling in dopaminergic neurons mediates neuroprotection in rodent models of Parkinson’s disease.
Publisher: SAGE Publications
Date: 2009
DOI: 10.1080/00048670903001984
Abstract: Objective: Young patients with frontotemporal dementia (FTD) may present with schizophrenia-like psychosis. Few studies have investigated whether FTD-like neuropathological changes are present in schizophrenia. The purpose of the present study was therefore to determine whether FTD-like abnormalities in TARDNA binding protein (TDP-43) and ubiquitin are detectable in hippoc al dentate gyrus of patients with schizophrenia and bipolar disorder. A secondary objective was to identify clinicopathological relationships of any such abnormalities. Methods: Hippoc al sections from 12 patients (nine with schizophrenia and three with bipolar disorder) and 11 control subjects Facility from the National Neural Tissue Resource Centre, Melbourne were blindly rated for the presence or absence of normal TDP-43 staining or ubiquitin-positive neuronal inclusions within the dentate gyrus. The clinical files of all subjects were reviewed for demographic and clinical information. Results: In three patients the normal expression of nuclear TDP-43 staining was not detected. Significantly, all three subjects presented after the age of 50 and had an adult child diagnosed with the same psychiatric disorder. Conclusion: Abnormalities in TDP-43 nuclear expression were identified in patients with late-onset psychosis and a positive family history.
Publisher: Elsevier BV
Date: 11-1995
Publisher: Springer Science and Business Media LLC
Date: 08-01-2018
Publisher: SAGE Publications
Date: 09-1994
DOI: 10.3109/00048679409075881
Abstract: A case of senile dementia of Lewy body type is presented. The clinical and neuropathological characteristics of the illness are discussed in the context of recent advances in the understanding of this condition.
Publisher: Wiley
Date: 03-2016
DOI: 10.1111/PDE.12826
Abstract: Discoid lupus erythematosus (DLE) is known to be associated with chronic granulomatous disease (CGD), but most DLE occurs in female carriers of X-linked CGD, with few reports of these lesions in CGD-affected in iduals--this observation is unexplained. We describe two cases of DLE-like lesions in boys with CGD: one boy with partial neutrophil function and another whose lesions were related to voriconazole use. Reviewing other previously reported cases, we conclude that the risk of developing DLE-like lesions appears to be greater primarily in two subsets of the population with CGD: those with partial neutrophil function and those with near-absent neutrophil function in whom there is a second trigger. In light of recent literature on the role of neutrophils in lupus pathogenesis, we propose that pathogenesis of DLE in CGD may be related to NETosis, neutrophil dysfunction and a deficiency of reactive oxygen species, which medications such as voriconazole also influence.
Publisher: Springer Science and Business Media LLC
Date: 07-07-2018
DOI: 10.1007/S00775-018-1590-4
Abstract: Age-associated deposition of amyloid-β in cerebral blood vessels, a condition referred to as cerebral amyloid angiopathy, can contribute to stroke and dementia. This research aimed to design new radioactive technetium-99 m complexes that bind to amyloid-β plaques that have the potential to assist in diagnosis of cerebral amyloid angiopathy using single-photon-emitted computed tomography (SPECT) imaging. Six new pyridylthiosemicarbazide ligands containing either benzofuran or styrylpyridyl functional groups that are known to selectively bind to amyloid plaques were prepared. Non-radioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. The new ligands were used to prepare well-defined [Re-oxo]
Publisher: Wiley
Date: 30-11-2017
DOI: 10.1111/PCMR.12544
Abstract: Metastasis represents the end product of an elaborate biological process, which is determined by a complex interplay between metastatic tumour cells, host factors and homoeostatic mechanisms. Cutaneous melanoma can metastasize haematogenously or lymphogenously. The three predominant models that endeavour to explain the patterns of melanoma progression are the stepwise spread model, the simultaneous spread model and the model of differential spread. The time course to the development of metastases differs between the different metastatic routes. There are several clinical and histopathological risk factors for the different metastatic pathways. In particular, patient sex and the anatomical location of the primary tumour influence patterns of disease progression. There is limited existing evidence regarding the relationship between tumour mutation status, other diagnostic and prognostic biomarkers and the metastatic pathways of primary cutaneous melanoma. This knowledge gap needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.JAAD.2016.08.009
Abstract: Scalp melanomas have more aggressive clinicopathological features than other melanomas and mortality rates more than twice that of melanoma located elsewhere. We sought to describe the survival of patients with scalp melanoma versus other cutaneous head and neck melanoma (CHNM), and explore a possible independent negative impact of scalp location on CHNM survival. A retrospective cohort study was performed of all invasive primary CHNM cases seen at a tertiary referral center over a 20-year period. Melanoma-specific survival (MSS) was compared between scalp melanoma and other invasive CHNM. Multivariable Cox proportional hazards regression was performed to determine associations with survival. On univariate analysis, patients with scalp melanoma had worse MSS than other CHNM (hazard ratio 2.22, 95% confidence interval 1.59-3.11). Scalp location was not associated with MSS in CHNM on multivariable analysis (hazard ratio 1.11, 95% confidence interval 0.77-1.61) for all tumors together, but remained independently associated with MSS for the 0.76- to 1.50-mm thickness stratum (hazard ratio 5.51, 95% confidence interval 1.55-19.59). Disease recurrence was not assessed because of unavailable data. The poorer survival of scalp melanoma is largely explained by greater Breslow thickness and a higher proportion of male patients.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 03-2022
Publisher: Wiley
Date: 22-11-2022
DOI: 10.1111/JNC.15713
Abstract: The two hallmarks of Alzheimer's disease (AD) are amyloid‐β (Aβ) plaques and neurofibrillary tangles marked by phosphorylated tau. Increasing evidence suggests that aggregating Aβ drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely, there is a realization that non‐fibrillar (oligomeric) forms of Aβ mediate toxicity in AD. Fibrillar (filamentous) aggregates of proteins across the spectrum of the primary and secondary tauopathies were the focus of recent structural studies with a filament structure‐based nosologic classification, but less emphasis was given to non‐filamentous co‐aggregates of insoluble proteins in the fractions derived from post‐mortem human brains. Here, we revisited sarkosyl‐soluble and ‐insoluble extracts to characterize tau and Aβ species by quantitative targeted mass spectrometric proteomics, biochemical assays, and electron microscopy. AD brain sarkosyl‐insoluble pellets were greatly enriched with Aβ 42 at almost equimolar levels to N‐terminal truncated microtubule‐binding region (MTBR) isoforms of tau with multiple site‐specific post‐translational modifications (PTMs). MTBR R3 and R4 tau peptides were most abundant in the sarkosyl‐insoluble materials with a 10‐fold higher concentration than N‐terminal tau peptides. This indicates that the major proportion of the enriched tau was the aggregation‐prone N‐terminal and proline‐rich region (PRR) of truncated mixed 4R and 3R tau with more 4R than 3R isoforms. High concentration and occupancies of site‐specific phosphorylation pT 181 (~22%) and pT 217 (~16%) (key biomarkers of AD) along with other PTMs in the PRR and MTBR indicated a regional susceptibility of PTMs in aggregated tau. Immunogold labelling revealed that tau may exist in globular non‐filamentous form (N‐terminal intact tau) co‐localized with Aβ in the sarkosyl‐insoluble pellets along with tau filaments (N‐truncated MTBR tau). Our results suggest a model that Aβ and tau interact forming globular aggregates, from which filamentous tau and Aβ emerge. These characterizations contribute towards unravelling the sequence of events which lead to end‐stage AD changes. image
Publisher: Elsevier BV
Date: 08-2010
Abstract: There is speculation that peripheral neuropathy (PN) with capecitabine and oxaliplatin (CapOx 130 mg/m(2), day 1, every 21 days) may be more common than with FOLFOX4 (5-fluorouracil and oxaliplatin 85 mg/m(2), day 1, every 14 days). We aimed to determine PN incidence and associations during CapOx, and 6 and 12 months after CapOx. Retrospective audit of 188 oxaliplatin-naive colorectal cancer patients (87 adjuvant, 101 palliative) who received at least one cycle of CapOx. Neurosensory Common Toxicity Criteria Adverse Events version 3 were applied. Overall, 94% experienced acute PN. Worst severities for adjuvant and palliative patients, respectively, were grade 1, 44% and 54% grade 2, 35% and 32% grade 3, 16% and 3% grade 4, 0% and 1% and grade unclear 1% and 1%. Two patients developed PN after CapOx completion despite no symptoms during treatment. Chronic PN at 6 months affected 57% and 18% of adjuvant and palliative patients, respectively. At 12 months, 35% and 16% were affected. Chronic PN at 12 months was associated with cumulative oxaliplatin dose but not age, gender, acute myotonia, pseudolaryngospasm or grade 2 or more PN during treatment. Incidence of acute PN during CapOx appears similar to FOLFOX4 but chronic PN in adjuvant patients may be more common with CapOx.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 2007
Abstract: Plasmablastic lymphoma is an AIDS related lymphoma that continues to have a poor prognosis despite significant advances in the management of HIV and lymphoproliferative diseases. In part this has been due to limited insights into the biology of this disease and the molecular mechanisms of oncogenesis. To date molecular abnormalities have not been described in plasmablastic lymphoma, and its aggressive clinical behaviour has been difficult to understand. We describe the first reported cytogenetic abnormality in plasmablastic lymphoma, an IgH/MYC translocation. It is also the first description of autologous stem cell transplantation in a patient with severe haemophilia A.
Publisher: Wiley
Date: 07-12-2007
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.NEUINT.2016.02.016
Abstract: Autophagy is a homeostatic process for recycling proteins and organelles that is increasingly being proposed as a therapeutic target for acute and chronic neurodegenerative diseases, including stroke. Confirmation that autophagy is present in the human brain after stroke is imperative before prospective therapies can begin the translational process into clinical trials. Our current study using human post-mortem tissue observed an increase in staining in microtubule-associated protein 1 light chain 3 (LC3), sequestosome 1 (SQSTM1 also known as p62) and the increased appearance of autophagic vesicles after stroke. These data confirm that alterations in autophagy take place in the human brain after stroke and suggest that targeting autophagic processes after stroke may have clinical significance.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2010
Publisher: Elsevier BV
Date: 08-1999
Publisher: Wiley
Date: 08-1999
Publisher: Elsevier BV
Date: 11-2017
Publisher: SAGE Publications
Date: 05-2001
Publisher: World Scientific Pub Co Pte Ltd
Date: 21-09-2015
DOI: 10.1142/S0218810415720193
Abstract: Fibro-osseous pseudotumour is a rare, benign ossifying tumour of soft tissue that should be considered in the differential diagnosis of any tumour affecting the digits. Clinical diagnosis is difficult and fibro-osseous pseudotumour is often mistaken for malignancy, leading to inappropriate treatment. Knowledge of its clinical and histopathological features thus allows for appropriate primary treatment, sparing the patient from unnecessary radical surgery associated with presumed malignancy. We present the case of a 48 year-old male with fibro-osseous pseudotumour affecting the right ring finger, successfully treated with local excision. This is the second reported Australian case of fibro-osseous pseudotumour, and we present an extensive review of the literature relating to the diagnosis and management of this rare tumour.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2017
DOI: 10.1007/S00702-016-1629-Z
Abstract: Parkinson's disease (PD) is a devastating disorder, affecting approximately 2% of people aged 60 and above. It is marked by progressive neurodegeneration that has long been known to impact dopaminergic cells and circuits, but more recently the acetylcholine system has also been implicated in the complex aetiology and symptomatology of the disease. While broad changes in cholinergic markers have been described, insight into the contribution of specific acetylcholine receptors is less clear. To address this important unknown, in this study we performed [
Publisher: Springer Science and Business Media LLC
Date: 23-10-2017
DOI: 10.1038/NG.3785
Publisher: SAGE Publications
Date: 22-09-2014
Abstract: FHL1 gene mutations are associated with reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy, Emery-Dreifuss muscular dystrophy, and isolated hypertrophic cardiomyopathy. We describe a boy with a family history consistent with X-linked distal myopathy/cardiomyopathy. The boy first presented at age 14 years and was found to have distal wasting and weakness. Echocardiogram revealed hypertrophic cardiomyopathy. Muscle biopsy showed a vacuolar pathology with no reducing bodies. Sequencing of FHL1 revealed a novel hemizygous c.764G C missense mutation in exon 8. This is the first report of a predominantly distal myopathy with hypertrophic cardiomyopathy occurring secondary to an FHL1 mutation.
Publisher: Elsevier BV
Date: 2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-03-2014
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.EXPNEUROL.2006.12.006
Abstract: Alpha-synuclein (alphaSN) is implicated in Parkinson's disease (PD) and is the major component of Lewy bodies (LBs). Although alphaSN is mainly expressed in neuronal cells and exists as a cytoplasmic protein, it has been found in body fluids including cerebrospinal fluid and blood. This study explored plasma alphaSN as a diagnostic marker for PD. Western blot analysis was used to characterize plasma alphaSN compared to brain alphaSN. Plasma alphaSN of 16 kDa migrates with the same mobility as its brain counterpart and recombinant alphaSN on denatured polyacrylamide gels and reacted with three different antibodies against the C-terminal and NAC regions of the alphaSN protein. The alphaSN levels in plasma from PD subjects are significantly lower than that in age-matched controls (p=0.001), and the alphaSN levels in patients with early-onset PD are lower than that in both late-onset PD and controls. This initial study indicates that measurement of alphaSN in plasma can provide support for a clinical diagnosis of Parkinson's disease and warrants further study in a larger population.
Publisher: Springer Science and Business Media LLC
Date: 16-06-2015
DOI: 10.1038/NCOMMS8247
Abstract: Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases ( n =152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT ( P =1.42 × 10 −12 ), 8p12 at lnc-KIF13B-1 , a long non-coding RNA (rs643472 P =3.41 × 10 −8 ), and 2p22 at SOS1 (rs963731 P =1.76 × 10 −7 ). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22 rs1768208 P =2.07 × 10 −7 ) and MAPT H1c (17q21 rs242557 P =7.91 × 10 −6 ). We previously reported SNP/transcript level associations with rs8070723/ MAPT , rs242557/ MAPT , and rs1768208/ MOBP and herein identified association with rs963731/ SOS1 . We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
Publisher: Springer Science and Business Media LLC
Date: 09-2002
Abstract: The apolipoprotein E (APOE, gene apoE, protein) type 4 isoform is a well-established risk factor for late-onset Alzheimer's disease (AD), and new data suggest that APOE promoter polymorphisms might also modulate AD risk, perhaps by altering transcription of the APOE gene. The current study was undertaken to determine whether the presence of the APOE promoter -491AA genotype (that appears to increase the risk for AD) is associated with an increase in the levels of apoE in brain tissue. Among 40 control and 20 autopsy-confirmed AD brain s les, levels of apoE were increased in the frontal cortex of AD cases (P < 0.001), consistent with the well-recognized up-regulation of APOE expression in reactive astrocytes. Among controls, the -491A allele appeared to impart a gene dose-dependent effect on the levels of apoE in frontal cortex. The levels of apoE in the brains of AD patients with the -491AA genotype were increased as compared to control subjects with the same genotype (P< 0.001). These data support the notion that the -491AA APOE promoter genotype is associated with elevated brain apolipoprotein E levels, suggesting that the risk for AD may be modulated by the apoE protein level as well as by the apoE protein isoform.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.NMD.2012.06.002
Abstract: The main diagnostic feature of congenital fibre type disproportion is that type 1 fibres are consistently smaller than type 2 fibres in the absence of other histological abnormalities. Mutations in the TPM3, RYR1 and ACTA1 genes are the most common established genetic causes. There has been one previous report of congenital fibre type disproportion due to a mutation in TPM2, although some atypical histological features were present. We present two cases in which novel de novo missense mutations in TPM2 are associated with marked fibre size disproportion. The finding of typical histological changes of congenital fibre type disproportion in association with a p.Ser61Pro mutation confirms that TPM2 can cause typical congenital fibre type disproportion. Although not seen on light microscopy studies, protein inclusions typical of small 'caps' were found on electron microscopy in a second patient with a p.Ala155Val mutation in TPM2. This case emphasises the importance of electron microscopy in patients with presumed congenital fibre type disproportion, to exclude the presence of caps, nemaline bodies or minicores, which, if present, may be very helpful in guiding genetic analysis.
Publisher: SAGE Publications
Date: 02-2013
DOI: 10.3851/IMP2451
Abstract: We report a challenging case of HIV-associated neurocognitive disorder with superimposed Epstein–Barr virus (EBV) encephalitis. The patient presented with an abnormal MRI brain scan, and EBV DNA that was detected in the cerebrospinal fluid and brain biopsy, which also demonstrated histopathological findings consistent with the diagnosis. This occurred on the background of a 12-month period of gradual cognitive decrease secondary to HIV-associated dementia. Invasive testing was required to reach the diagnosis in this case, highlighting the importance of thorough investigation of neurological impairment in HIV-positive patients. Clinicopathological recovery was achieved through optimization of antiretroviral therapy and use of valganciclovir.
Publisher: Elsevier BV
Date: 02-2011
Publisher: Elsevier BV
Date: 11-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-09-2008
Publisher: Wiley
Date: 11-08-2022
DOI: 10.1002/RCR2.1021
Abstract: Pulmonary alveolar proteinosis (PAP) is a rare lung disease where there is accumulation of surfactant in the alveoli. It can be classified based on the underlying aetiology into three categories: primary, secondary and congenital. Autoantibodies to granulocyte‐macrophage colony‐stimulating factor (GM‐CSF‐Ab) are a key diagnostic feature of autoimmune PAP. High intensity occupational exposure and inhalation of toxic particles such as silica can cause a form of secondary PAP called acute silicoproteinosis. We describe a 26‐year‐old stone benchtop fabricator with silicoproteinosis following daily exposure to high levels of silica who had elevated serum GM‐CSF‐Ab. We discuss the role of GM‐CSF‐Ab in cases of PAP with occupational inhalational exposure and the challenges in its interpretation.
Publisher: Wiley
Date: 16-08-2006
Publisher: American Chemical Society (ACS)
Date: 26-07-2016
DOI: 10.1021/ACS.INORGCHEM.6B00972
Abstract: Alzheimer's disease is characterized by the presence of amyloid plaques in the brain. The primary constituents of the plaques are aggregated forms of the amyloid-β (Aβ) peptide. With the goal of preparing technetium-99(m) complexes that bind to Aβ plaques with the potential to be diagnostic imaging agents for Alzheimer's disease, new tetradentate ligands capable of forming neutral and lipophilic complexes with oxotechentium(V) and oxorhenium(V) were prepared. Nonradioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. Two planar tetradentate N3O ligands were prepared that form charge-neutral complexes with oxorhenium(v) as well as a ligand featuring a styrylpyridyl functional group designed to bind to Aβ plaques. All three ligands formed complexes with oxorhenium(V), and each complex was characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The oxorhenium(V) complex with a styrylpyridyl functional group binds to Aβ plaques present in post-mortem human brain tissue. The chemistry was extrapolated to technetium-99(m) at the tracer level for two of the ligands. The resulting oxotechnetium(V) complexes were sufficiently lipophilic and charge-neutral to suggest that they have the potential to cross the blood-brain barrier but exhibited modest stability with respect to exchange with histidine. The chemistry presented here identifies a strategy to integrate styrylpyridyl functional groups into tetradentate ligands capable of forming complexes with [M═O](3+) cores (M = Re or Tc).
Publisher: American Association for the Advancement of Science (AAAS)
Date: 25-02-0033
Abstract: The tumor-suppressor PTPN2 is diminished in a subset of triple-negative breast cancers (TNBCs). Paradoxically, PTPN2-deficiency in tumors or T cells in mice can facilitate T cell recruitment and/or activation to promote antitumor immunity. Here, we explored the therapeutic potential of targeting PTPN2 in tumor cells and T cells. PTPN2-deficiency in TNBC associated with T cell infiltrates and PD-L1 expression, whereas low PTPN2 associated with improved survival. PTPN2 deletion in murine mammary epithelial cells TNBC models, did not promote tumorigenicity but increased STAT-1–dependent T cell recruitment and PD-L1 expression to repress tumor growth and enhance the efficacy of anti-PD-1. Furthermore, the combined deletion of PTPN2 in tumors and T cells facilitated T cell recruitment and activation and further repressed tumor growth or ablated tumors already predominated by exhausted T cells. Thus, PTPN2-targeting in tumors and/or T cells facilitates T cell recruitment and/or alleviates inhibitory constraints on T cells to combat TNBC.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.4158/EP10213.CR
Publisher: Oxford University Press (OUP)
Date: 12-05-2014
DOI: 10.1093/EHJCI/JEU077
Abstract: In hypertrophic cardiomyopathy (HCM), attempts to associate genotype with phenotype have largely been unsuccessful. More recently, cardiac magnetic resonance (CMR) imaging has enhanced myocardial fibrosis characterization, while next-generation sequencing (NGS) can identify pathogenic HCM mutations. We used CMR and NGS to explore the link between genotype and fibrotic phenotype in HCM. One hundred and thirty-nine patients with HCM and 25 healthy controls underwent CMR to quantify regional myocardial fibrosis with late gadolinium enhancement (LGE) and diffuse myocardial fibrosis with post-contrast T1 mapping. Collagen content of myectomy specimens from nine HCM patients was determined. Fifty-six HCM patients underwent NGS for 65 cardiomyopathy genes, including 36 HCM-associated genes. Post-contrast myocardial T1 time correlated histologically with myocardial collagen content (r = -0.70, P = 0.03). Compared with controls, HCM patients had more LGE (4.6 ± 6.1 vs. 0%, P < 0.001) and lower post-contrast T1 time (483 ± 83 vs. 545 ± 49 ms, P < 0.001). LGE negatively correlated with left-ventricular (LV) ejection fraction and outflow tract obstruction, whereas lower post-contrast T1 time, suggestive of more diffuse myocardial fibrosis, was associated with LV diastolic impairment and dyspnoea. Patients with identifiable HCM mutations had more LGE (7.9 ± 8.6 vs. 3.1 ± 4.3%, P = 0.03), but higher post-contrast T1 time (498 ± 81 vs. 451 ± 70 ms, P = 0.03) than patients without. In HCM, contrast-enhanced CMR with T1 mapping can non-invasively evaluate regional and diffuse patterns of myocardial fibrosis. These patterns of fibrosis occur independently of each other and exhibit distinct clinical associations. HCM patients with recognized genetic mutations have significantly more regional, but less diffuse myocardial fibrosis than those without.
Publisher: Oxford University Press (OUP)
Date: 04-2014
DOI: 10.1111/BJD.12780
Abstract: Recurrent naevi are widely recognized to occur commonly following incomplete removal of melanocytic lesions. These lesions have been generally understood as representing benign imitators of melanoma. To provide a formal description of the clinical findings of postexcisional melanocytic regrowth. We examined all cases of recurrent pigmentation adjacent to scars from previous excisional biopsies of melanocytic naevi treated at a private dermatology practice from 1995 to 2012. We report nine cases of recurrence of melanocytic lesions that were melanomas. The most suspicious clinical feature for melanoma in these cases was the growth of the lesion beyond the confines of the initial scar, into the surrounding normal skin. This pattern of recurrence of a melanocytic lesion represents a little recognized and distinctive clinical presenting sign of melanoma.
Publisher: MDPI AG
Date: 10-02-2023
DOI: 10.3390/IJMS24043582
Abstract: We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known in idual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this in idual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.
Publisher: SAGE Publications
Date: 07-1994
DOI: 10.1177/088307389400900320
Abstract: Idiopathic hypothalamic dysfunction is a rare but well-defined entity in childhood characterized by adipsia-hypernatremia, obesity, poor thermoregulation, and disturbance of pituitary function. Two cases of idiopathic hypothalamic dysfunction are described. There are 10 previously reported cases in the literature, and the clinical features are compared. The present cases are unique in that the patients also had bilaterally dilated unresponsive pupils. In the first case, there was no demonstrable pathology at autopsy in the second case, lymphocytic infiltration of the hypothalamus and midbrain associated with neuronal loss was present at autopsy. Possible etiologies are discussed. (J Child Neurol 1994 :320-325).
Publisher: Springer International Publishing
Date: 2015
Publisher: Wiley
Date: 31-10-2007
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.NMD.2009.03.003
Abstract: Cap disease or cap myopathy is a form of congenital myopathy in which peripheral, well-demarcated 'caps' of disorganised thin filaments are seen in muscle fibres. Mutation of the TPM2 gene, that encodes beta-tropomyosin, is the first reported genetic cause. In this paper, we describe a further case of cap disease due to a mutation in TPM2, confirming the importance of this genetic association. This is the first report of cardiac dysfunction due to a mutation in TPM2. Our patient has an identical TPM2 mutation to the first genetically diagnosed cap disease patient, a denovo heterozygous three base pair deletion that removes glutamic acid 139 from the centre of beta-tropomyosin (p.E139del). 2D-gel electrophoresis studies show that the shortened mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2017
DOI: 10.1038/BJC.2017.253
Publisher: Elsevier BV
Date: 06-2000
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S0006-3223(02)01976-5
Abstract: Apolipoprotein E (apoE) has been implicated in the pathology of AD ever since inheritance of the epsilon4 allele was shown to be an important risk factor for the development of AD. Apolipoprotein D (apoD) is elevated in association with several central nervous system disorders, including Alzheimer's disease (AD), and has been proposed to be an especially robust marker for brain regions specifically affected by particular neuropathologies. Progressive cognitive decline is the core clinical feature of AD and is associated with disturbances in the prefrontal cortex. We measured apoD levels in prefrontal cortex s les obtained postmortem from 20 autopsy-confirmed AD subjects and 40 control subjects. Enzyme-linked immunosorbent assay analysis revealed a significant increase in apoD expression in AD subjects compared with control subjects (.218+/-.029 microg/mg protein vs.117+/-.011 microg/mg protein p=0003). There was no significant difference in apoD expression between early-onset and late-onset Alzheimer's subjects. Apolipoprotein D expression levels were not correlated with apoE levels, nor were they correlated with inheritance of the APOE epsilon4 allele. These findings suggest that apoD may be related to the cognitive decline observed in AD patients and that apoD and apoE likely play different roles in the pathogenesis of AD.
Publisher: Wiley
Date: 12-2018
DOI: 10.1111/IMJ.14126
Publisher: Springer Science and Business Media LLC
Date: 08-08-2017
DOI: 10.1038/BJC.2017.254
Publisher: Springer Science and Business Media LLC
Date: 09-2004
DOI: 10.1007/S00415-004-0489-X
Abstract: Tau gene mutations with insoluble Tau neuropathology have been identified in pedigrees with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Other neurodegenerative diseases, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are also characterised by insoluble Tau neuropathology. This study sought to determine the nature and frequency of tau gene mutations in an affected proband cohort of patients within this spectrum of neurodegenerative diseases. Sixty-four in iduals with clinical features consistent with FTD and other tauopathies were referred over a three year period. There was neuropathological confirmation of disease in 30%. In iduals were screened for mutations in the coding region and flanking intronic regions of the tau gene by direct sequencing of PCR products. Four confirmed tau gene mutations were identified representing 6.3 % for the total affected proband cohort. Tau gene mutations were found in three of twelve (25%) of the cases with a family history of dominantly inherited frontotemporal dementia, but in only one of 25 cases without a family history (4 %). Although tauopathies have been considered to result from genetic defects, screening for tau gene mutations in sporadic cases is not likely to identify pathogenic mutations.
Publisher: AMPCo
Date: 10-2017
DOI: 10.5694/MJA17.00232
Abstract: To determine the frequency of naevus-associated melanoma among superficial spreading and nodular subtypes and to investigate associations between naevus-associated melanoma and other clinico-pathological characteristics. Cross-sectional study of all patients with nodular and superficial spreading melanomas diagnosed between 1994 and 2015 at the Victorian Melanoma Service, Melbourne. Clinical and pathological characteristics of naevus-associated and de novo melanomas were assessed in univariable and multivariable logistic regression analyses. Of 3678 primary melanomas, 1360 (37.0%) were histologically associated with a naevus and 2318 (63.0%) were de novo melanomas 71 of 621 nodular (11.4%) and 1289 of 3057 superficial spreading melanomas (42.2%) were histologically associated with a naevus. In multivariable analyses, the odds of being associated with a naevus were higher for melanomas located on the trunk (v head and neck: adjusted odds ratio [OR], 2.27 95% CI, 1.73-2.96 P < 0.001), while the odds were lower for thicker tumours (adjusted OR, 0.75 per millimetre increase in Breslow thickness 95% CI, 0.69-0.81 P < 0.001), amelanotic/hypomelanotic melanomas (adjusted OR, 0.68 95% CI, 0.48-0.97 P = 0.035), and older age (patients 70 years or older v patients under 30 at diagnosis: adjusted OR, 0.28 95% CI, 0.20-0.40 P < 0.001). After adjusting for confounders, the odds of an associated naevus was three times as high for superficial spreading melanomas as for nodular melanomas (adjusted OR, 3.05 95% CI, 2.24-4.17 P < 0.001). Melanomas are most likely to arise in the absence of a pre-existing naevus, particularly nodular melanomas. Public health c aigns should therefore emphasise the detection of suspicious de novo lesions, as well as of changing lesions.
Publisher: Wiley
Date: 03-05-2007
Publisher: Wiley
Date: 02-2012
DOI: 10.1111/J.1445-2197.2011.05979.X
Abstract: The histological characteristics of follicular thyroid carcinomas (FTCs) are important predictors of prognosis, and lesions can be classified as either minimally invasive follicular carcinoma (MIFC) or widely invasive follicular carcinoma (WIFC) based on histopathological characteristics. There has been controversy surrounding the histological classification of FTC, which can present challenges to clinicians attempting to deliver accurate prognostic information to their patients. The aim of the present study was to examine cases of metastatic FTC for characteristics that may predict aggressive tumour behaviour. The Monash University Endocrine Surgery Unit database was searched for patients with FTC. The histopathology reports were collated for these patients to confirm the diagnosis of FTC, classify patients into MIFC versus WIFC, and examine for key characteristics such as the capsular and/or vascular invasion. The thyroid specimens from patients with metastatic FTC were examined by reviewing pathologists. It was hypothesized that patients with metastatic disease would likely have WIFC as their primary lesion. There were 64 patients with FTC identified during the period of 1997-2009. Of these, 10 patients were found to have metastatic disease. On review of the histopathology, three patients were found to have WIFC,four patients had MIFC and three patients did not have definite features of FTC found in the thyroid gland. Currently accepted histological classification of FTC is inadequate and fails to accurately predict patients with distant metastatic disease and a more aggressive clinical course. It is thus the policy of our unit to recommend total thyroidectomy and radioactive iodine ablation for all patients with FTC.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2015
DOI: 10.1038/SREP14764
Abstract: Microglia-mediated neuroinflammation may play an important role in the initiation and progression of dopaminergic (DA) neurodegeneration in Parkinson’s disease (PD) and toll-like receptor 4 (TLR4) is essential for the activation of microglia in the adult brain. However, it is still unclear whether patients with PD exhibit an increase in TLR4 expression in the brain and whether there is a correlation between the levels of prothrombin kringle-2 (pKr-2) and microglial TLR4. In the present study, we first observed that the levels of pKr-2 and microglial TLR4 were increased in the substantia nigra (SN) of patients with PD. In rat and mouse brains, intranigral injection of pKr-2, which is not directly toxic to neurons, led to the disruption of nigrostriatal DA projections. Moreover, microglial TLR4 was upregulated in the rat SN and in cultures of the BV-2 microglial cell line after pKr-2 treatment. In TLR4-deficient mice, pKr-2-induced microglial activation was suppressed compared with wild-type mice, resulting in attenuated neurotoxicity. Therefore, our results suggest that pKr-2 may be a pathogenic factor in PD and that the inhibition of pKr-2-induced microglial TLR4 may be protective against degeneration of the nigrostriatal DA system in vivo .
Publisher: Elsevier BV
Date: 10-2011
Publisher: Wiley
Date: 16-09-2014
DOI: 10.1111/ADJ.12220
Abstract: Myeloid sarcoma, also commonly termed granulocytic sarcoma or chloroma, is a rare condition involving infiltration of immature myeloid cells in an extramedullary site. Myeloid sarcoma is often related to leukaemia however, the condition can also occur in association with various myeloproliferative disorders. Although myeloid sarcoma can occur in any body part, involvement of the neoplastic condition in the oral cavity is infrequent with only 37 cases reported in the literature. We will describe two cases of oral myeloid sarcoma observed at The Alfred Hospital's Dental Unit and discuss their presenting features, diagnosis and subsequent management.
Publisher: Wiley
Date: 29-04-2002
DOI: 10.1046/J.1471-4159.2002.00902.X
Abstract: Previous studies have shown that a minor glycoform of acetylcholinesterase (AChE) is increased in Alzheimer's disease brain and cerebrospinal fluid. This glycoform can be distinguished from other AChE species by its lack of binding to concanavalin A (Con A). In this study, the temporal relationship between AChE glycosylation and Abeta deposition was examined in Tg2576 mice. There was a significant (p < 0.05) difference in AChE glycosylation in Tg2576 mice compared with age-matched background strain control mice at 4 months of age. This difference in glycosylation was also observed in 8- and 12-month-old Tg2576 mice. In contrast, Abeta plaques were only seen in the Tg2576 mice at 12 months of age, and were not detected at 4 and 8 months of age. Soluble human-sequence Abeta was detected as early as 4 months of age in the transgenic mice. The altered AChE glycosylation was due to an increase in a minor AChE isoform, which did not bind Con A, similar to that previously observed to be increased in Alzheimer's disease brain and cerebrospinal fluid. The results demonstrate that in transgenic mice altered AChE glycosylation is associated with very early events in the development of AD-like pathology. The study supports the possibility that glycosylation may also be a useful biomarker of AD.
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 02-2011
Abstract: The authors report the first case of extensive craniocervical pneumocranium causing mass effect, without any associated extradural pneumatocele. The patient presented with frontal headaches and unusual sensations in his left ear. He was found to have large pneumocranium involving his left frontal, temporal, parietal, and occipital bones as well as the atlas. He underwent a craniectomy with replacement of the pneumatized bone with titanium mesh, and mastoidectomy with obliteration of the mastoid air cells. This case is discussed in the context of the literature to date. A review of the literature shows that trauma is not a common cause of pneumocranium, with most cases occurring spontaneously. The authors believe that a combined neurosurgical-otological approach is beneficial in such cases.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.JAUT.2016.03.017
Abstract: The properties of CD4(+) regulatory T cell (Treg) subsets are dictated by distinct patterns of gene expression determined by FOXP3 and different combinations of various transcription factors. Here we show the NF-κB transcription factor RelA is constitutively active in naïve and effector Tregs. The conditional inactivation of Rela in murine FOXP3(+) cells induces a rapid onset, multi-focal autoimmune disease that depends on RelA being expressed in conventional T cells. In addition to promoting Treg lineage stability, RelA determines the size of the effector Treg population, a function influenced by the presence or absence of RelA in conventional T cells. These findings showing that RelA controls Treg stability and promotes the competitive fitness of effector Tregs highlight the importance of RelA activity in peripheral Treg induced tolerance.
Publisher: Wiley
Date: 08-12-2015
DOI: 10.1002/CAM4.355
Publisher: Oxford University Press (OUP)
Date: 18-09-2013
DOI: 10.1093/HMG/DDT449
Abstract: Utrophin is a potential therapeutic target for the fatal muscle disease, Duchenne muscular dystrophy (DMD). In adult skeletal muscle, utrophin is restricted to the neuromuscular and myotendinous junctions and can compensate for dystrophin loss in mdx mice, a mouse model of DMD, but requires sarcolemmal localization. NFATc1-mediated transcription regulates utrophin expression and the LIM protein, FHL1 which promotes muscle hypertrophy, is a transcriptional activator of NFATc1. By generating mdx/FHL1-transgenic mice, we demonstrate that FHL1 potentiates NFATc1 activation of utrophin to ameliorate the dystrophic pathology. Transgenic FHL1 expression increased sarcolemmal membrane stability, reduced muscle degeneration, decreased inflammation and conferred protection from contraction-induced injury in mdx mice. Significantly, FHL1 expression also reduced progressive muscle degeneration and fibrosis in the diaphragm of aged mdx mice. FHL1 enhanced NFATc1 activation of the utrophin promoter and increased sarcolemmal expression of utrophin in muscles of mdx mice, directing the assembly of a substitute utrophin-glycoprotein complex, and revealing a novel FHL1-NFATc1-utrophin signaling axis that can functionally compensate for dystrophin.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Oxford University Press (OUP)
Date: 28-10-2014
DOI: 10.1093/EHJCI/JEU182
Abstract: Myocardial fibrosis is fundamental in the pathogenesis of heart failure. Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) imaging is commonly assumed to represent myocardial fibrosis however, comparative human histological data are limited, especially in non-ischaemic cardiac disease. Diffuse interstitial myocardial fibrosis is increasingly recognized as central in the pathogenesis of cardiomyopathy and can be quantified using newer CMR techniques such as T1 mapping. We evaluated the relationship of CMR assessment of regional and diffuse fibrosis with human histology. Eleven patients on the waiting list for heart transplantation (43.5 ± 7.6 years, 64% male) and eight patients undergoing surgical myectomy for obstructive hypertrophic cardiomyopathy (57.1 ± 8.6 years, 63% male) were recruited and underwent CMR prior to cardiac transplantation or myectomy. Quantification of fibrosis in explanted hearts using digitally analysed Masson-trichrome-stained slides was validated against picrosirius red-stained slides analysed using Image J, with an excellent correlation (R = 0.95, P < 0.0001). Significant correlations were observed between LGE and histological fibrosis across a range of signal intensity thresholds in the explanted hearts (range: 2-10 standard deviations above reference myocardium), with maximal accuracy at a threshold of 6 SD (R = 0.91, P < 0.001). Assessment of interstitial myocardial fibrosis with post-contrast T1 times demonstrated a significant correlation on both segmental (R = -0.64, P = 0.002) and per-patient (R = -0.78, P = 0.003) analyses. CMR provides accurate, non-invasive assessment of regional myocardial fibrosis using LGE, while diffuse interstitial myocardial fibrosis is accurately assessed with post-contrast T1 mapping.
Publisher: Wiley
Date: 11-2001
DOI: 10.1046/J.1471-4159.2001.00640.X
Abstract: A number of biomarkers (e.g. Abeta, tau) has been identified in Alzheimer's disease CSF. However, none fulfils the criteria of sensitivity and specificity (> 80%) needed for the development of an accurate diagnostic test. The lack of a suitable marker has prompted the search for new CSF biomarkers. In this study, the glycosylation of CSF proteins was examined using lectin blotting. Lumbar CSF was collected ante mortem from 22 non-Alzheimer's disease and 12 probable Alzheimer's disease cases and ventricular CSF collected post mortem from 7 non-Alzheimer's disease and 16 Alzheimer's disease cases confirmed by pathologic examination. When CSF glycoproteins were stained with wheat germ agglutinin (WGA), the staining intensity was found to be significantly lower in the Alzheimer's disease group. No difference in staining was found using other lectins (Canavalia ensiformis agglutinin, Ricinus communis agglutinin, Lens culinaris agglutinin). The measurement of WGA-reactive glycoproteins in CSF may be a useful biomarker for diagnosis of Alzheimer's disease.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.CCELL.2015.07.003
Abstract: Metastasis is the major cause of breast cancer mortality. Phosphoinositide 3-kinase (PI3K) generated PtdIns(3,4,5)P3 activates AKT, which promotes breast cancer cell proliferation and regulates migration. To date, none of the inositol polyphosphate 5-phosphatases that inhibit PI3K/AKT signaling have been reported as tumor suppressors in breast cancer. Here, we show depletion of the inositol polyphosphate 5-phosphatase PIPP (INPP5J) increases breast cancer cell transformation, but reduces cell migration and invasion. Pipp ablation accelerates oncogene-driven breast cancer tumor growth in vivo, but paradoxically reduces metastasis by regulating AKT1-dependent tumor cell migration. PIPP mRNA expression is reduced in human ER-negative breast cancers associated with reduced long-term outcome. Collectively, our findings identify PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.CELREP.2012.08.026
Abstract: Cellular injury causes a myriad of processes that affect proteostasis. We describe nucleocytoplasmic coagulation (NCC), an intracellular disulfide-dependent protein crosslinking event occurring upon late-stage cell death that orchestrates the proteolytic removal of misfolded proteins. In vitro and in vivo models of neuronal injury show that NCC involves conversion of soluble intracellular proteins, including tubulin, into insoluble oligomers. These oligomers, also seen in human brain tissue following neurotrauma, act as a cofactor and substrate for the plasminogen-activating system. In plasminogen(-/-) mice, levels of misfolded β-tubulin were elevated and its clearance delayed following neurotrauma, demonstrating a requirement for plasminogen in the removal of NCC constituents. While additional in vivo studies will further dissect this phenomenon, our study clearly shows that NCC, a process analogous to the formation of thrombi, generates an aggregated protein scaffold that limits release of cellular components and recruits clearance mechanisms to the site of injury.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.EJON.2015.02.007
Abstract: The aim of this study was to evaluate the late effects and quality of life of patients following chemo-radiation treatment for anal cancer. All surviving anal cancer patients treated within NHS Lothian between 1990 and 2007 were invited to participate. Data were collected using the EORTC QLQ-C30, the EORTC QLQ-CR38 and the Memorial Sloan-Kettering Cancer Centre Bowel Function Instrument (MSKCC). Overall response rate was 46% (n = 42) mean age 54.7 years and with a median time interval of 63.8 months between treatment and completion of the questionnaires. Thirty-five percent of the participants were 'rarely' or 'never' able to wait 15 min to get to the toilet 50% were 'rarely' or 'never' able to control the passage of gas 35% limited the types of solid foods they eat 22% had leakage of stool during the day 39% required to use a protective pad and 29% altered their daily activities because of bowel function 'always' or 'most of the time'. Seventeen percent of patients reported financial difficulties ('quite a bit' and 'very much'). Both men and women reported high symptomology for sexual problems with a median score of 83.3 (50.0. 100.0). This study has shown that in a sub-set of patients treated with chemo-radiation for anal cancer, persistent treatment related issues are reported at a medium time interval of 5.3 years. Further work is now required to understand the impact of symptoms on day-to-day life and the challenges that people face in managing these inter-related and complex problems.
Publisher: Wiley
Date: 08-2006
DOI: 10.1111/J.1540-8159.2006.00447.X
Abstract: In this study, we aimed to compare the level of atrial sympathetic innervation in human atrial fibrillation (AF) to that in sinus rhythm (SR). Histological studies of atrial tissue obtained from animals with experimentally induced AF indicate that sympathetic hyperinnervation could play a role in the pathogenesis of AF. In 24 patients (12 in SR and 12 in AF) undergoing bypass surgery, we collected right atrial appendage tissue. In AF patients, left atrial appendage tissue was also acquired. The degree of sympathetic innervation was quantified by measuring the amount of staining for tyrosine hydroxylase (TH) and tissue norepinephrine (NE). In conjunction, nerve growth factor (NGF) mRNA expression was assessed by real-time polymerase chain reaction (PCR). Growth-associated protein 43 (GAP43) immunostaining was used to assess degree of new neural growth. When corrected for differences in tissue fibrosis, the expression of both TH (AF 0.45 +/- 0.1%, SR 0.09 +/- 0.03%, P = 0.02) and tissue NE (AF 358 +/- 49 pg/mg, SR 225 +/- 39 pg/mg, P = 0.04) was greater in atrial tissue of the AF cohort. The degree of atrial TH staining (P = 0.01) and NE content (P < 0.001) was also significantly greater in the right compared with left atrial s les in the AF cohort. There were no differences in NGF mRNA expression or GAP43 staining. This study provides evidence for the presence of heightened atrial sympathetic innervation in patients with persistent AF, suggesting autonomic remodeling may be part of atrial substrate for AF.
Publisher: Elsevier BV
Date: 09-2010
Publisher: Wiley
Date: 02-2015
DOI: 10.1111/AJD.12293
Abstract: Information on the prognosis for patients with regional cutaneous melanoma metastases has been sparse and difficult to establish. In 2009 the American Joint Committee on Cancer (AJCC) melanoma staging has for the first time provided survival rates for patients who manifest intralymphatic metastases. We sought to validate the new staging system in this contemporary, prospectively collected cohort of patients following the development of cutaneous metastases as the first evidence of metastatic disease and explored the factors that influenced their prognosis. The Victorian Melanoma Service database was searched to identify all patients with cutaneous melanoma metastases. Patients who were found to have lymph node or visceral metastases at the time they were diagnosed with cutaneous metastatic disease were excluded. Survival curves were generated and univariate and multivariate assessments of prognostic factors associated with survival were performed. In total, 72 patients presented with cutaneous metastases as the first evidence of metastatic disease. The median melanoma-specific survival of patients with only regional cutaneous metastases (n = 56) was 5.07 years and their 5-year survival rate was 52%. Distant cutaneous metastases and thickness of the primary melanoma were found to be significant negative predictors of survival. We were able to validate the new AJCC melanoma staging system survival for patients with cutaneous metastatic disease. Patients presenting with regional cutaneous metastases have a much better prognosis than those with distant cutaneous metastases.
Publisher: Elsevier BV
Date: 08-2004
Publisher: Elsevier BV
Date: 11-2013
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.TRANSPROCEED.2014.09.149
Abstract: Preservation of donor hearts for transplantation has traditionally been performed with the use of static cold storage. We have developed and tested a novel gravity-powered system of cold crystalloid perfusion for prolonged donor heart preservation. Greyhounds were anesthetized their hearts were arrested with cold cardioplegic solution and excised. Hearts were allocated to 12 hours of perfusion preservation (n = 6) or cold storage in ice (n = 5). Non-preserved hearts (n = 5) served as a normal reference group. Perfusion hearts were perfused (20 mL/min, 8-12°C) with a novel oxygenated nutrient-containing preservation solution. After preservation, the recovery of the hearts was assessed in a blood-perfused working heart rig over 2 hours in terms of function, blood lactate level, myocardial adenosine triphosphate, and histology. After 2 hours of reperfusion, in comparison with cold storage hearts, perfused heart function curves showed superior recovery of cardiac output (P = .001), power (P = .001), and efficiency (0.046 ± 0.01 vs 0.004 ± 0.003 joules/mL O2, P = .034). Myocardial adenosine triphosphate content (mmol/mg protein) was reduced significantly from the normal level of 26.5 (15.9, 55.8) to 5.08 (0.50, 10.4) (P = .049) in cold storage hearts but not in perfused hearts. Over a period of 2 hours, lactate levels in the blood perfusate were significantly lower in the perfusion group than in the cold storage group (P < .05). Continuous hypothermic crystalloid perfusion provides myocardial preservation superior to cold storage for long-term heart preservation, with potential applicability to marginal and donation after circulatory death hearts.
Publisher: AMPCo
Date: 03-2012
DOI: 10.5694/MJA11.10894
Publisher: Wiley
Date: 10-08-2009
DOI: 10.1111/J.1471-4159.2009.06233.X
Abstract: Postmortem human brain tissue is widely used in neuroscience research, but use of tissue originating from different brain bank centers is considered inaccurate because of possible heterogeneity in s le quality. There is thus a need for well-characterized markers to assess the quality of postmortem brain tissue. Toward this aim, we determined tryptophan (TRP) concentrations, phosphofructokinase-1 and glutamate decarboxylase activities in 119 brain tissue s les. These neurochemical parameters were tested in s les from autopsied in iduals, including control and pathological cases provided by 10 different brain bank centers. Parameters were assessed for correlation with agonal state, postmortem interval, age and gender, brain region, preservation and freezing methods, storage conditions and storage time, RNA integrity, and tissue pH value. TRP concentrations were elevated significantly (p = 0.045) with increased postmortem interval which might indicate increased protein degradation. Therefore, TRP concentration might be one useful and convenient marker for estimating the quality of human postmortem brain tissue.
Publisher: Frontiers Media SA
Date: 13-08-2014
Publisher: Wiley
Date: 21-05-2015
DOI: 10.1002/RCR2.104
Publisher: Wiley
Date: 23-11-2004
DOI: 10.1002/ANA.20304
Abstract: We molecularly characterized human immunodeficiency virus type 1 (HIV-1) present in pure populations of astrocytes, macrophages, and multinucleated giant cells isolated using laser capture microdissection from brain tissue of two patients who died with HIV-associated dementia. The V3 region of the HIV-1 envelope (env) gene was lified from the pure-cell populations, and multiple clones were sequenced. In both patients, the V3 env sequences were distinct in astrocytes compared with neighboring macrophages or multinucleated giant cells and were characteristic of CCR5-using (R5) HIV-1. These results demonstrate cell-specific compartmentalization of distinct R5-like viral strains in the central nervous system microenvironment.
Publisher: Wiley
Date: 29-08-2018
DOI: 10.1111/NAN.12514
Abstract: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.
Publisher: American Society for Clinical Investigation
Date: 04-01-2021
DOI: 10.1172/JCI135124
Publisher: Oxford University Press (OUP)
Date: 13-06-2014
DOI: 10.1093/HMG/DDU300
Publisher: American Society of Hematology
Date: 30-04-2015
DOI: 10.1182/BLOOD-2014-09-603555
Abstract: INPP4B promotes chemoresistance in AML independent of phosphoinositide phosphatase function.
Publisher: Wiley
Date: 27-10-2011
Publisher: Wiley
Date: 2001
DOI: 10.1046/J.1471-4159.2001.00021.X
Abstract: Intracellular inclusions containing alpha-synuclein (alpha SN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In order to identify disease-associated changes of alpha SN, this study compared the levels, solubility and molecular weight species of alpha SN in brain homogenates from MSA, DLB, PD and normal aged controls. In DLB and PD, substantial amounts of detergent-soluble and detergent-insoluble alpha SN were detected compared with controls in grey matter homogenate. Compared with controls, MSA cases had significantly higher levels of alpha SN in the detergent-soluble fraction of brain s les from pons and white matter but detergent-insoluble alpha SN was not detected. There was an inverse correlation between buffered saline-soluble and detergent-soluble levels of alpha SN in in idual MSA cases suggesting a transition towards insolubility in disease. The differences in solubility of alpha SN between grey and white matter in disease may result from different processing of alpha SN in neurons compared with oligodendrocytes. Highly insoluble alpha SN is not involved in the pathogenesis of MSA. It is therefore possible that buffered saline-soluble or detergent-soluble forms of alpha SN are involved in the pathogenesis of other alpha SN-related diseases.
Publisher: Future Medicine Ltd
Date: 08-2012
DOI: 10.2217/FVL.12.70
Abstract: Aims: HIV-1 infection represents the most common immunosuppressive condition associated with progressive multifocal leukoencephalopathy (PML). Materials & methods: Nested PCR and quantitative real-time PCR (qPCR) for JC virus (JCV) DNA was performed on serial plasma s les obtained from 14 HIV patients with PML and 27 matched controls. Results: JCV large T antigen (LT) DNA was detected via qPCR in 11 out of 14 (79%) PML patients at disease onset and four out of 27 (15%) controls (p 0.001). JCV LT qPCR was associated with PML diagnosis, duration of known HIV infection, absence of a prior AIDS-defining illness and absence of combination antiretroviral therapy (p 0.001 R 2 = 0.35). JCV LT qPCR was more likely to be positive in the 8 months prior to PML diagnosis compared with earlier s les (p = 0.01). Conclusion: Detection of JCV DNA in plasma of HIV infected patients via qPCR may represent a valuable test for identifying patients at risk of developing PML.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.JOCN.2015.08.042
Abstract: Angiitis of the central nervous system (CNS) is difficult to diagnose but potentially fatal. When stroke occurs in a younger in idual or is associated with multiple infarcts on imaging, clinicians must decide how far to pursue a possible diagnosis of vasculitis. The aim of this study is to establish the prevalence of primary and secondary cerebral angiitis among patients presenting with stroke. Hospital attendances over a 10year period were surveyed by searching for diagnostic codes and key words specific for cerebral vasculitis/angiitis. Case notes were reviewed by the authors using two sets of criteria for angiitis of the CNS. Thirty-two patients were initially considered likely to have cerebral angiitis by treating physicians. Thirteen had been admitted to hospital with stroke. During this period, there were 7475 admissions for ischaemic and haemorrhagic stroke. Six patients had a final diagnosis of vasculitic stroke but only one had definite CNS angiitis with a first presentation as ischaemic stroke (0.02%). Most patients who did have cerebral vasculitis developed multifocal or subacute neurological deficits, or already had an immunological disorder known to be associated with secondary CNS angiitis. Of 19 patients given an alternative final diagnosis, the most common were atherosclerotic/embolic cerebrovascular disease (n=9) and reversible cerebral vasoconstriction syndrome (n=7). Stroke is rarely the first manifestation of cerebral vasculitis. Our findings suggest that routine screening for angiitis in stroke patients may not be warranted.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-03-2023
DOI: 10.1212/NXG.0000000000200064
Abstract: Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the dystrophin gene ( DMD ). Hypermethylated CGG expansions within DIP2B 5′ UTR are associated with an intellectual development disorder. Here, we demonstrate the diagnostic utility of genomic short-read sequencing (SRS) and transcriptome sequencing to identify a novel DMD structural variant (SV) and a DIP2B CGG expansion in a patient with DMD for whom conventional diagnostic testing failed to yield a genetic diagnosis. We performed genomic SRS, skeletal muscle transcriptome sequencing, and targeted programmable long-read sequencing (LRS). The proband had a typical DMD clinical presentation, autism spectrum disorder (ASD), and dystrophinopathy on muscle biopsy. Transcriptome analysis identified 6 aberrantly expressed genes DMD and DIP2B were the strongest underexpression and overexpression outliers, respectively. Genomic SRS identified a 216 kb paracentric inversion (NC_000023.11: g.33162217-33378800) overlapping 2 DMD promoters. ExpansionHunter indicated an expansion of 109 CGG repeats within the 5′ UTR of DIP2B . Targeted genomic LRS confirmed the SV and genotyped the DIP2B repeat expansion as 270 CGG repeats. Here, transcriptome data heavily guided genomic analysis to resolve a complex DMD inversion and a DIP2B repeat expansion. Longitudinal follow-up will be important for clarifying the clinical significance of the DIP2B genotype.
Publisher: Wiley
Date: 15-08-2005
DOI: 10.1111/J.1445-5994.2005.00877.X
Abstract: The prevalence of hepatitis C virus (HCV) infection in adult patients with a congenital bleeding disorder (CBD) approaches 95% and is a major cause of morbidity and mortality. Histological examination of the liver remains the cornerstone of management decisions in patients without a CBD. The reluctance to perform liver biopsies in patients with a CBD has been a major limitation in the management of these patients. We are currently the only haemophilia centre in Australasia performing liver biopsies in patients with a CBD for the purpose of guiding prognostic and therapeutic decisions. We report here the results of our centre's experience with transjugular liver biopsy (TJLB) in patients with a CBD. An adequate specimen for histological assessment was attained from all of the patients. There were no major complications recorded. Patients were hospitalized for < or = 48 h for haemostasis prophylaxis. The diagnostic specimen obtained from patients was integral in guiding their future management. We suggest that with a coordinated multidisciplinary approach, TJLB can be performed in patients with a CBD.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4DT02969K
Abstract: [M(CO) 3 ] + (M = Tc/Re) complexes with tridentate ligands with a stilbene functional group bind to amyloid-β plaques associated with Alzheimer's Disease.
Publisher: Oxford University Press (OUP)
Date: 05-04-2017
DOI: 10.1093/BRAIN/AWX057
Abstract: We fractionated frontal cortical grey matter from human Alzheimer's disease and control subjects into four biochemically defined pools that represent four distinct compartments: soluble/cytosolic, peripheral membrane/vesicular cargo, integral lipid/membranous pools and aggregated/insoluble debris. Most of the readily extractable amyloid-β remains associated with a lipid/membranous compartment. There is an exchange of amyloid-β between the biochemical pools that was lost for the amyloid-β42 species in Alzheimer's disease, consistent with the peptide being irreversibly trapped in extracellular deposits. The quantitative amyloid-β data, combined with magnetic resonance imaging volumetric analysis of the amount of cortical grey matter in brain, allowed us to estimate the total mass of amyloid-β in Alzheimer's disease (6.5 mg) and control (1.7 mg) brains. The threshold positron emission tomography standard uptake value ratio of 1.4 equates to 5.0 μg amyloid-β/g of grey matter and the mean Alzheimer's disease dementia standard uptake value ratio level of 2.3 equates to 11.20 μg amyloid-β/g of grey matter. It takes 19 years to accumulate amyloid from the threshold positron emission tomography standard uptake value ratio to the mean value observed for Alzheimer's disease dementia. This accumulation time window combined with the difference of 4.8 mg of amyloid-β between Alzheimer's disease and control brain allows for a first approximation of amyloid-β accumulation of 28 ng/h. This equates to an estimated 2-5% of the total amyloid-β production being deposited as insoluble plaques. Understanding these rates of amyloid-β accumulation allows for a more quantitative approach in targeting the failure of amyloid-β clearance in sporadic Alzheimer's disease.
Publisher: Wiley
Date: 17-06-2016
DOI: 10.1002/IJC.30150
Publisher: Springer Science and Business Media LLC
Date: 03-08-2018
DOI: 10.1007/S11695-017-2859-3
Abstract: Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are endemic in obesity. We aimed to evaluate the diagnostic accuracy and reproducibility of a simple intraoperative visual liver score to stratify the risk of NASH and NAFLD in obesity and determine the need for liver biopsy. This is a prospective cohort study of obese adults undergoing bariatric surgery. The surgical team used a visual liver score to evaluate liver colour, size and surface. This was compared to histology from an intraoperative liver biopsy. There were 152 participants, age 44.6 ± 12 years, BMI 45 ± 8.3 kg/m A simple, structured tool based on liver appearance can be a useful and reliable tool for NAFLD risk stratification and identification of patients who would most and least benefit from a biopsy. A normal liver appearance reliably excludes significant liver disease, avoiding the need for liver biopsy in patients otherwise at high clinical risk of NASH.
Publisher: Society for Neuroscience
Date: 18-05-2016
DOI: 10.1523/JNEUROSCI.4261-15.2016
Abstract: Lipocalin-2 (LCN2) is a member of the highly heterogeneous secretory protein family of lipocalins and increases in its levels can contribute to neurodegeneration in the adult brain. However, there are no reports on the role of LCN2 in Parkinson's disease (PD). Here, we report for the first time that LCN2 expression is increased in the substantia nigra (SN) of patients with PD. In mouse brains, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment for a neurotoxin model of PD significantly upregulated LCN2 expression, mainly in reactive astrocytes in both the SN and striatum. The increased LCN2 levels contributed to neurotoxicity and neuroinflammation, resulting in disruption of the nigrostriatal dopaminergic (DA) projection and abnormal locomotor behaviors, which were ameliorated in LCN2-deficient mice. Similar to the effects of MPTP treatment, LCN2-induced neurotoxicity was also observed in the 6-hydroxydopamine (6-OHDA)-treated animal model of PD. Moreover, treatment with the iron donor ferric citrate (FC) and the iron chelator deferoxamine mesylate (DFO) increased and decreased, respectively, the LCN2-induced neurotoxicity in vivo . In addition to the in vivo results, 1-methyl-4-phenylpyridinium (MPP + )-induced neurotoxicity in cocultures of mesencephalic neurons and astrocytes was reduced by LCN2 gene deficiency in the astrocytes and conditioned media derived from MPP + -treated SH-SY5Y neuronal enhanced glial expression of LCN2 in vitro . Therefore, our results demonstrate that astrocytic LCN2 upregulation in the lesioned DA system may play a role as a potential pathogenic factor in PD and suggest that inhibition of LCN2 expression or activity may be useful in protecting the nigrostriatal DA system in the adult brain. SIGNIFICANCE STATEMENT Lipocalin-2 (LCN2), a member of the highly heterogeneous secretory protein family of lipocalins, may contribute to neuroinflammation and neurotoxicity in the brain. However, LCN2 expression and its role in Parkinson's disease (PD) are largely unknown. Here, we report that LCN2 is upregulated in the substantia nigra of patients with PD and neurotoxin-treated animal models of PD. Our results suggest that LCN2 upregulation might be a potential pathogenic mechanism of PD, which would result in disruption of the nigrostriatal dopaminergic system through neurotoxic iron accumulation and neuroinflammation. Therefore, inhibition of LCN2 expression or activity may be useful in protecting the nigrostriatal dopaminergic projection in PD.
Publisher: Wiley
Date: 07-11-2017
DOI: 10.1002/ACN3.487
Publisher: Microbiology Society
Date: 06-2005
Abstract: Two typical coliforms from an intestinal biopsy from an adult case of bloody diarrhoea carried genes encoding intimin-beta, stx(1) and ehxA, and produced verocytotoxin 1 and enterohaemolysin in culture. Both were biochemically typical Escherichia coli O5 :H(-), apart from producing urease. Such O5 isolates represent a human pathogenic E. coli lineage.
Publisher: Springer Science and Business Media LLC
Date: 12-2017
Publisher: Springer Science and Business Media LLC
Date: 23-10-2017
DOI: 10.1038/NATURE24284
Publisher: Springer Science and Business Media LLC
Date: 07-05-2014
DOI: 10.1007/S00401-014-1290-2
Abstract: Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.PARKRELDIS.2012.07.010
Abstract: Corticobasal syndrome (CBS), which encompasses cortical sensory loss, alien limb, bradykinesia, rigidity, limb apraxia and dystonia, is the classic presentation of corticobasal degeneration (CBD). It may occur in other neurodegenerative disorders including sporadic Creutzfeldt-Jakob disease (sCJD). Current CBD diagnostic criteria outline features of CBS but fail to distinguish CBD from other causative pathologies. To characterise the CBS presentation of sCJD (sCJD-CBS) in the context of existing CBD diagnostic criteria. Data of two new cases of sCJD-CBS and seven patients identified from the Australian National Creutzfeldt-Jakob Disease Registry database was reviewed. Additional data from 11 published cases was incorporated to illustrate the natural history of sCJD-CBS. Comparison was made with pathologically diagnosed CBD cases with ante-mortem CBS presentation (CBD-CBS). sCJD-CBS accounts for 1.8% of all Australian sCJD cases. Compared to CBD-CBS, disease progression is more rapid in sCJD-CBS (median time to diagnosis 48 vs.1.5 months, p < 0.001 and disease duration until death 68 vs. 5 months, p < 0.001). Although no clinical features separate the two, alien limb and myoclonus tend to occur early in sCJD-CBS following initial 'sensory' disturbance in the affected limb. Consistent with sCJD, distinctive diffusion weighted imaging (DWI) abnormalities on magnetic resonance imaging may also occur in sCJD-CBS. sCJD should be suspected in patients presenting with CBS when clinical progression is rapid and accompanied by DWI abnormalities, even without cerebrospinal fluid 14-3-3 protein detection and electroencephalographic periodic sharp wave complexes. We propose the addition of rapid (<12 months) progression to akinetic-mutism or death and DWI abnormalities as exclusions in future CBD diagnostic criteria.
Publisher: Springer Science and Business Media LLC
Date: 10-12-2015
Publisher: Society for Neuroscience
Date: 25-02-2015
DOI: 10.1523/JNEUROSCI.3439-14.2015
Abstract: Elevation of both neuronal iron and nitric oxide (NO) in the substantia nigra are associated with Parkinson's disease (PD) pathogenesis. We reported previously that the Alzheimer-associated β-amyloid precursor protein (APP) facilitates neuronal iron export. Here we report markedly decreased APP expression in dopaminergic neurons of human PD nigra and that APP −/− mice develop iron-dependent nigral cell loss. Conversely, APP-overexpressing mice are protected in the MPTP PD model. NO suppresses APP translation in mouse MPTP models, explaining how elevated NO causes iron-dependent neurodegeneration in PD.
Publisher: Elsevier BV
Date: 11-2018
Publisher: MDPI AG
Date: 21-10-2021
Abstract: Lipocalin-2 (LCN2) is an inflammatory protein with erse functions in the brain. Although many studies have investigated the mechanism of LCN2 in brain injuries, the effect of LCN2 on amyloid-toxicity-related memory deficits in a mouse model of Alzheimer’s disease (AD) has been less studied. We investigated the role of LCN2 in human AD patients using a mouse model of AD. We created an AD mouse model by injecting amyloid-beta oligomer (AβO) into the hippoc us. In this model, animals exhibited impaired learning and memory. We found LCN2 upregulation in the human brain frontal lobe, as well as a positive correlation between white matter ischemic changes and serum LCN2. We also found increased astrocytic LCN2, microglia activation, iron accumulation, and blood–brain barrier disruption in AβO-treated hippoc i. These findings suggest that LCN2 is involved in a variety of amyloid toxicity mechanisms, especially neuroinflammation and oxidative stress.
Publisher: Oxford University Press (OUP)
Date: 19-09-2011
Publisher: Wiley
Date: 26-07-2017
Publisher: Wiley
Date: 10-03-2004
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.CORTEX.2015.03.011
Abstract: Logopenic progressive aphasia is one of the clinical presentations of primary progressive aphasia and formally defined by the co-occurrence of impaired naming and sentence repetition. Impaired naming is attributed to failure of lexical retrieval, which is a multi-staged process subserved by anatomically segregated brain regions. By dissecting the neurocognitive processes involved in impaired naming, we aimed to disentangle the clinical and neuroanatomical heterogeneity of this syndrome. Twenty-one in iduals (66.7% females, age range 53-83 years) who fulfilled diagnostic criteria for logopenic variant and had at least two clinical and language assessments, 1 year apart, were recruited and matched for age, sex distribution and level of education with a healthy control s le (n = 18). All participants underwent a structural brain scan at the first visit and surface-wise statistical analysis using Freesurfer. Seventeen participants with logopenic variant underwent amyloid imaging, with 14 demonstrating high amyloid retention. Based on their performance on single-word comprehension, repetition and confrontation naming, three subgroups of logopenic cases with distinctive linguistic profiles and distribution of atrophy were identified. The first subgroup (n = 10) demonstrated pure anomia and left-sided atrophy in the posterior inferior parietal lobule and lateral temporal cortex. The second subgroup (n = 6), presented additional mild deficits in single-word comprehension, and also exhibited bilateral thinning of the fusiform gyri. The third subgroup (n = 5) showed additional impaired single-word repetition, and cortical thinning focused on the left superior temporal gyrus. The subgroups differed in the proportion of cases with high amyloid retention and in the rate of decline of naming performance over time, suggesting that neurodegeneration spreads differentially throughout regions subserving word processing. In line with previous reports, these results confirm the extensive damage to the language network and, in part, explain the clinical heterogeneity observed across logopenic cases.
Publisher: Wiley
Date: 13-12-2016
DOI: 10.1111/JCMM.13044
Publisher: Springer Science and Business Media LLC
Date: 2001
Publisher: Oxford University Press (OUP)
Date: 18-07-2012
DOI: 10.1093/BRAIN/AWS178
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-03-2007
DOI: 10.1212/01.WNL.0000256819.61531.98
Abstract: A 62-year-old Indonesian woman presenting with a progressive supranuclear palsy-like syndrome was confirmed post mortem as dying from a spongiform encephalopathy. Despite an illness duration of only 4 months, brain MRI, EEG, and CSF analysis for 14-3-3 proteins all failed to disclose changes typical of Creutzfeldt-Jakob disease. Neuropathologic examination revealed multicentric, prion protein-positive, amyloid plaques as typically seen in Gerstmann-Sträussler-Scheinker syndrome. Prion protein gene analysis revealed a previously unreported A133V mutation.
Location: Australia
No related grants have been discovered for Catriona McLean.