ORCID Profile
0000-0002-1196-0926
Current Organisation
University of South Australia
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Publisher: Wiley
Date: 04-09-1997
DOI: 10.1002/(SICI)1097-0215(19970904)72:5<860::AID-IJC24>3.0.CO;2-B
Abstract: Consumption of soy products has been linked to a reduced mortality and morbidity from a number of cancers. Genistein, one of the principal soy isoflavones, has been shown to inhibit the growth of a number of tumour cell lines in vitro however, a role of genistein in retarding tumour growth in vivo is less well documented. In this study, in addition to examining the effects of genistein on the growth of murine B16 melanoma cells in vitro, we have examined the effects of feeding a genistein-rich diet on s.c. growth of these tumour cells in mice. In vitro, the melanoma cells showed an increase in sensitivity to genistein with increasing time of exposure, culminating in a 50% growth inhibition (IC50) at 12.5 microM after 7 days. Genistein at 25 microM induced micronucleus formation after 24 hr and at concentrations as low as 2.5 microM induced morphological changes indicative of differentiation. Growth of solid tumours implanted into female C57BL/6J mice was inhibited by 50% when mice were fed genistein for 1 week before and for 1 week after inoculation with B16 melanoma cells. Plasma genistein concentrations at the time of tumour removal were 1.1 microM, which is similar to levels reported in humans consuming diets high in soybeans or soybean products, while control animals had no detectable genistein in plasma. Our results provide additional in vivo evidence suggesting that genistein retards the growth of implanted tumours, adding further to studies suggesting that this isoflavonoid is a biologically active component of soy foods.
Publisher: Wiley
Date: 07-1995
DOI: 10.1111/J.1440-1681.1995.TB02050.X
Abstract: 1. The levels of the neurotrophic factor, nerve growth factor (NGF) in the mesenteric vascular bed of the spontaneously hypertensive rat (SHR) were greater than those in the corresponding vascular bed of normotensive Wistar‐Kyoto rats (WKY). 2. Administration of angiotensin II (200 ng/kg per min, by minipump) for 2 weeks to juvenile WKY rats increased the levels of NGF in the mesenteric vasculature to those seen in untreated SHR. 3. Administration of the angiotensin II receptor antagonists losartan (30 mg/kg per day, p.o.) or PD144277 (10 mg/kg per day, p.o.) to juvenile SHR for 4 weeks reduced the levels of NGF such that they were indistinguishable from the values obtained for normotensive WKY rats. 4. The results confirm the elevated level of NGF in the mesenteric vasculature of the SHR and suggest that angiotensin II may play a role in regulating the abnormal concentrations of the protein in this tissue.
Publisher: Springer Science and Business Media LLC
Date: 1996
DOI: 10.1007/BF00226781
Abstract: Early attachment shapes brain development underlying emotion regulation. Given that sensitivity to affective cues is heightened during adolescence and effective emotion regulation strategies continue to develop, it is imperative to examine the role of early attachment and parental influence on adolescent regulation. Fifty-one children (M age=32.61 months) participated in a modified Strange Situation with their mother and approximately 10 years later (M age =13.2 years) completed an fMRI scan during which they were presented with appetitive and aversive affective cues (images of adolescent interactions) during a Go-Nogo task. They completed the task alone and in the presence of a parent. Behavioral multilevel models and whole-brain analyses showed attachment-related patterns, such that affective cues elicited greater behavioral and neural dysregulation in insecure (versus secure) adolescents.Furthermore, parental presence buffered behavioral and neural dysregulation toward socially aversive cues for adolescents with early insecure attachment, underscoring the salience of caregivers across development in promoting regulation in their offspring.
Publisher: Elsevier BV
Date: 11-2013
Publisher: Wiley
Date: 02-1976
DOI: 10.1038/ICB.1976.4
Abstract: Electrolysis of 3-methoxycatecholamines in physiological solutions resulted in the formation of the parent catecholamines and their oxidation products. Conversion occurred at the anode. Maximal catecholamine production occurred in the presence of ascorbic acid.
Publisher: MDPI AG
Date: 25-09-2022
DOI: 10.3390/PH15101186
Abstract: The global burden of cancer necessitates rapid and ongoing development of effective cancer therapies. One promising approach in this context is the repurposing of existing non-cancer drugs for cancer indications. A key to this approach is selecting the cellular targets against which to identify novel repurposed drugs for pre-clinical analysis. Protein kinases are highly sought-after anticancer drug targets since dysregulation of kinases is the hallmark of cancer. To identify potential kinase-targeted drug candidates from the existing portfolio of non-cancer therapeutics, we used combined in silico and in vitro approaches, including ligand-based 3D screening followed by biochemical and cellular assessments. This strategy revealed that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In view of previous findings implicating Aurora A kinase in abnormal cell cycle regulation, we also examined the influence of rilpivirine on the growth of T47D breast cancer cells. Herein, we detail the identification of rilpivirine as an Aurora A kinase inhibitor, its molecular basis of inhibitory activity towards this kinase, and its Aurora A-mediated anticancer mechanisms in T47D cells. Our results illustrate the value of integrated in silico and in vitro screening strategies in identifying repurposed drug candidates and provide a scientific basis for further exploring the potential anticancer properties of the anti-viral drug rilpivirine.
Publisher: Elsevier BV
Date: 08-2001
Publisher: Wiley
Date: 03-1994
DOI: 10.1111/J.1440-1681.1994.TB02496.X
Abstract: 1. The effects of 5-hydroxytryptamine (5-HT) in the absence and presence of noradrenaline (NA) or the thromboxane-A2 mimetic, U44069, were investigated in ring preparations of marmoset aorta. 2. 5-HT (0.001-10 mumol/L) produced little or no contractile response in preparations at basal tone. When the tone was elevated to 50% of maximum with NA the predominant response to 5-HT was relaxation. The 5-HT2 receptor antagonist LY53857 (0.1 mumol/L) unmasked a contractile response to low concentrations of 5-HT (0.01-1.0 mumol/L) and reduced relaxation to high concentrations of 5-HT (1.0-10 mumol/L) in vessels precontracted with NA. 3. In U44069-contracted vessels, 5-HT was contractile in the range 0.01-1 mumol/L and relaxant in concentrations of 6.0-10.0 mumol/L. Ketanserin (1.0 mumol/L) had no effect on the contraction or relaxation to 5-HT. 4. The relaxant response to 5-HT was not significantly diminished in endothelium-impaired arteries. 5. In conclusion, 5-HT exerts complex inhibitory and excitatory actions on the marmoset aorta. The inhibitory actions are not endothelium-dependent and the excitatory actions do not appear to involve the 5-HT2 receptor.
Publisher: Elsevier BV
Date: 03-1972
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/08037059409101528
Abstract: The mRNA expression of renin, angiotensinogen and angiotensin converting enzyme (ACE) was determined in the kidneys and livers from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) during chronic treatment with captopril and following its withdrawal. Chronic captopril treatment was associated with a dramatic rise in renin mRNA in the kidney and an elevation in mRNA for ACE in the liver. The release from captopril treatment was associated with a reversal of the increase in kidney renin mRNA but no reversal of the sustained elevation of ACE mRNA in the liver. In situ hybridisation revealed a localisation of renin to the area of the juxtaglomerular apparatus in the kidneys from untreated animals, but recruitment of vascular sites of renin expression in kidneys from captopril-treated animals. In kidneys from released animals, renin mRNA expression was once again confined to the juxtaglomerular apparatus. ACE mRNA was expressed in hepatocytes throughout the livers from animals in all treatment groups. The results highlight a differential effect of captopril withdrawal upon the gene expression of the components of the renin-angiotensin system in kidney and liver.
Publisher: Elsevier BV
Date: 02-1992
DOI: 10.1016/0014-2999(92)90538-F
Abstract: There is a large body of evidence to suggest that the sympathetic nervous system plays a critical role in the development of hypertension and vascular medial hypertrophy in the spontaneously hypertensive rat (SHR). The synthesis of a water soluble, specific alpha 1-adrenoceptor antagonist (terazosin) has permitted an examination of the influence of alpha 1-adrenoceptors on those two phenomena. Thus, in the present study, terazosin (43 mg/kg per day) was administered to SHR and Wistar-Kyoto (WKY) rats from 4.5 to 12 weeks of age, and a number of assessments made in vitro and in vivo. In the SHR, the development of hypertension was not prevented by terazosin. The drug did not influence blood pressure in the WKY. This was despite the fact that animals which had been chronically treated with terazosin displayed marked alpha-adrenoceptor blockade in vivo. The response of systolic blood pressure to tyramine and noradrenaline was significantly reduced in animals which had been chronically treated with terazosin. In both the SHR and WKY, chronic administration of terazosin did not influence vascular concentrations of 3-methylhistidine, a biochemical marker for contractile proteins and vascular medial hypertrophy. The results therefore argue against a role of alpha 1-adrenoceptors in the development of hypertension and vascular medial hypertrophy in the SHR.
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/08037059409101525
Abstract: We have previously shown cheek cell Na+/H+ antiporter activity to be reduced in human hypertensives. We have now examined the relationship between abnormal antiporter activity and a variety of salivary factors. Total protein concentration and amylase activity were higher in hypertensives, but salivary flow rate and epidermal growth factor, transforming growth factor-alpha, calcium, and magnesium concentrations were not significantly different between hypertensives and normotensives. The lowered cheek cell Na+/H+ antiporter activity in those hypertensives with diastolic BP greater than 95 mmHg was accompanied by lowered salivary Na+/H+ ratios. In borderline hypertensives (diastolic BP between 90 and 95 mmHg), the Na+/H+ ratio was reduced to a similar extent to that seen in those hypertensives with a diastolic BP above 95 mmHg, however the cheek cell antiporter activity was not reduced, suggesting that these two differences are not related in a simple fashion in all hypertensives. It is concluded that it is unlikely that differences in salivary growth factors explain the lowered cheek cell Na+/H+ antiporter activity observed in human hypertension. Our findings indicate that salivary electrolyte composition may be related to cheek cell Na+/H+ antiporter activity and these parameters may be altered in hypertension.
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/08037059409101524
Abstract: Recent evidence in rats has indicated that angiotensinogen may be synthesised in adipose tissue surrounding blood vessels and that a local renin-angiotensin system may regulate adipose tissue blood supply and the efflux of fatty acids from fat in that species. This hypothesis is critically dependent on the local expression of the angiotensin converting enzyme gene in adipocytes. Thus the current study set out to examine whether the angiotensin converting enzyme gene was expressed in human adipose tissue and, if it was present, to localise the in idual sites of that expression. Northern analysis indicated the presence of mRNA for angiotensin converting enzyme in both subcutaneous and extraperitoneal adipose tissue. In situ hybridisation showed that the gene was expressed in adipocytes. The foregoing results therefore suggest that components of the renin-angiotensin cascade are also present in human adipose tissue and support the hypothesis that adipose tissue may play a role in the local production of Angiotensin II and hence participate in vascular function and blood pressure control in the human.
Publisher: Springer Science and Business Media LLC
Date: 09-1986
DOI: 10.1007/BF00498735
Abstract: Hispanic/Latino populations possess a complex genetic structure that reflects recent admixture among and potentially ancient substructure within Native American, European, and West African source populations. Here, we quantify genome-wide patterns of SNP and haplotype variation among 100 in iduals with ancestry from Ecuador, Colombia, Puerto Rico, and the Dominican Republic genotyped on the Illumina 610-Quad arrays and 112 Mexicans genotyped on Affymetrix 500K platform. Intersecting these data with previously collected high-density SNP data from 4,305 in iduals, we use principal component analysis and clustering methods FRAPPE and STRUCTURE to investigate genome-wide patterns of African, European, and Native American population structure within and among Hispanic/Latino populations. Comparing autosomal, X and Y chromosome, and mtDNA variation, we find evidence of a significant sex bias in admixture proportions consistent with disproportionate contribution of European male and Native American female ancestry to present-day populations. We also find that patterns of linkage-disequilibria in admixed Hispanic/Latino populations are largely affected by the admixture dynamics of the populations, with faster decay of LD in populations of higher African ancestry. Finally, using the locus-specific ancestry inference method LAMP, we reconstruct fine-scale chromosomal patterns of admixture. We document moderate power to differentiate among potential subcontinental source populations within the Native American, European, and African segments of the admixed Hispanic/Latino genomes. Our results suggest future genome-wide association scans in Hispanic/Latino populations may require correction for local genomic ancestry at a subcontinental scale when associating differences in the genome with disease risk, progression, and drug efficacy, as well as for admixture mapping.
Publisher: Springer Science and Business Media LLC
Date: 10-07-2009
DOI: 10.1007/S10620-008-0379-7
Abstract: The aim of this study was to design food grade matrices to deliver microencapsulated fish oil to the large bowel of the rat where the potential exists to retard inflammation and cancer development. Digestion in simulated gastric fluid and intestinal fluid demonstrated that only 4-6% of oil was released from the following dried emulsion formulations: 50% fish oil encapsulated in heated casein-glucose-dried glucose syrup (1:1:1) (Cas-Glu-DGS-50) 25% fish oil in casein-modified resistant starch (Hylon VII) (1:1) (Cas-Hylon-25) or 25% fish oil in Cas-Glu-Hylon (1:1:1) (Cas-Glu-Hylon-25). A short-term gavage study (0-12 h) with fish oil and Cas-Glu-DGS-50 demonstrated the appearance of fish oil long chain (LC) n-3 polyunsaturated fatty acids (PUFA) into the plasma indicating specific small intestinal absorption with little LC n-3 PUFA reaching the large bowel. In a 2-week-long term, daily gavage study, the bioavailability of fish oil and fish oil in Cas-Glu-DGS-50 or Cas-Hylon-25 demonstrated that fish oil and Cas-Glu-DGS-50 LC n-3 PUFA were incorporated into the tissue of the small intestine and colon, whereas Cas-Hylon-25 was resistant to degradation in the small intestine. The use of modified Hylon VII for targeted colonic delivery was confirmed in the final short-term gavage study (0-14 h) using Cas-Glu-Hylon-25 with [(14)C]-trilinolenin as a marker incorporated into the microcapsules, where up to 60% of the labeled oil reached the large bowel. Depending on the microencapsulating matrix employed, fish oil can be delivered selectively to the small intestine or to a high degree to the large bowel.
Publisher: S. Karger AG
Date: 1985
DOI: 10.1159/000158601
Abstract: We have measured the catecholamine (CA) contents in hearts, mesenteric vasculature, abdominal aorta, inferior vena cava, vasa deferentia and salivary glands from genetically hypertensive rats (SHR) and normotensive Kyoto-Wistar rats (WKY). We noted differences between the norepinephrine (NE) contents of in idual tissues from SHR and WKY rats and have used two different analytical procedures for the measurement of NE to confirm these differences. Comparisons between tissue contents of NE in SHR and WKY rats indicated a greater content of NE in the following tissues from the SHR: heart, mesenteric artery, abdominal aorta, inferior vena cava and vasa deferentia. A modest elevation of NE [but not epinephrine (E)] was observed in adrenal glands from SHR rats. The NE contents of salivary glands from SHR and WKY rats were indistinguishable from each other. The results suggest that there may exist a generalized increase in NE contents in the peripheral vasculature of SHR rats. Furthermore, this increase is also present in the vasa deferentia, but not the salivary gland. The results draw attention to altered concentrations of NE in vascular and selected nonvascular tissues in the SHR.
Publisher: Springer Science and Business Media LLC
Date: 1985
DOI: 10.1007/BF00695185
Abstract: Therapy for multiple myeloma (MM) has markedly changed in the past decade with the introduction of new drugs, but it is not clear whether the improvements have been sustained. We studied 1038 patients diagnosed between 2001 and 2010, grouping patients into two 5-year periods by diagnosis, 2001-2005 and 2006-2010. The median estimated follow-up for the cohort was 5.9 years with 47% alive at the last follow-up. The median overall survival (OS) for the entire cohort was 5.2 years: 4.6 years for patients in the 2001-2005 group compared with 6.1 years for the 2006-2010 cohort (P=0.002). The improvement was primarily seen among patients over 65 years, the 6-year OS improving from 31 to 56%, P<0.001. Only 10% of patients died during the first year in the latter group, compared with 16% in the earlier cohort (P<0.01), suggesting improvement in early mortality. The improved outcomes were linked closely to the use of one or more new agents in initial therapy. The current results confirm continued survival improvement in MM and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival is benefitting older patients and that early mortality in this disease has reduced considerably.
Publisher: Wiley
Date: 09-07-2022
DOI: 10.1111/BCP.14964
Abstract: Repurposing the large arsenal of existing non‐cancer drugs is an attractive proposition to expand the clinical pipelines for cancer therapeutics. The earlier successes in repurposing resulted primarily from serendipitous findings, but more recently, drug or target‐centric systematic identification of repurposing opportunities continues to rise. Kinases are one of the most sought‐after anti‐cancer drug targets over the last three decades. There are many non‐cancer approved drugs that can inhibit kinases as “off‐targets” as well as many existing kinase inhibitors that can target new additional kinases in cancer. Identifying cancer‐associated kinase inhibitors through mining commercial drug databases or new kinase targets for existing inhibitors through comprehensive kinome profiling can offer more effective trial‐ready options to rapidly advance drugs for clinical validation. In this review, we argue that drug repurposing is an important approach in modern drug development for cancer therapeutics. We have summarized the advantages of repurposing, the rationale behind this approach together with key barriers and opportunities in cancer drug development. We have also included ex les of non‐cancer drugs that inhibit kinases or are associated with kinase signalling as a basis for their anti‐cancer action.
Publisher: Bentham Science Publishers Ltd.
Date: 11-05-2016
DOI: 10.2174/1567205013666160315112151
Abstract: Alzheimer's disease (AD) is a degenerative brain disorder and is the most common form of dementia. Minimally invasive approaches are required that combine biomarkers to identify in iduals who are at risk of developing mild cognitive impairment (MCI) and AD, to appropriately target clinical trials for therapeutic discovery as well as lifestyle strategies aimed at prevention. Buccal mucosa cells from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing cohort (n=60) were investigated for cytological markers that could be used to identify both MCI and AD in iduals. Visual scoring of the buccal cytome demonstrated a significantly lower frequency of basal and karyorrhectic cells in the MCI group compared with controls. A high content, automated assay was developed using laser scanning cytometry to simultaneously measure cell types, nuclear DNA content and aneuploidy, neutral lipid content, putative Tau and amyloid-β (Aβ) in buccal cells. DNA content, aneuploidy, neutral lipids and Tau were similar in all groups. However, there was significantly lower Tau protein in both basal and karyolytic buccal cell types compared with differentiated buccal cells. Aβ, as measured by frequency of cells containing Aβ signal, as well as area and integral of Aβ signal, was significantly higher in the AD group compared with the control group. Buccal cell Aβ was correlated with mini-mental state examination (MMSE) scores (r = -0.436, P=0.001) and several blood-based biomarkers. Combining newly identified biomarkers from buccal cells with those already established may offer a potential route for more specific biomarker panels which may substantially increase the likelihood of better predictive markers for earlier diagnosis of AD.
Publisher: S. Karger AG
Date: 1995
DOI: 10.1159/000159099
Abstract: Treatment of spontaneously hypertensive rats (SHR) with alpha-adrenoceptor antagonists failed to alter the development of hypertension in this animal model. However, agents such as captopril (CAP) and losartan (LOS) which interfere with the renin-angiotensin system effectively prevented the development of hypertension. When tolerance occurred in the presence of doxazosin (DOX) or phenoxybenzamine, there was an enhanced sensitivity to the blood pressure lowering influence of LOS. In the presence of CAP, at a dose that did not retard the development of blood pressure in the SHR, DOX treatment significantly offset the development of hypertension in this strain. These results suggest that a functional tolerance to agents that interfere with the sympathetic nervous system is mediated by the renin-angiotensin system. Angiotensin-converting enzyme inhibition was associated with a normalization of the enhanced contraction of the mesenteric vascular bed seen in preparations from the SHR and a suppression in the development of the vascular lifier. The results suggest that the sympathetic nervous system is unable to maintain an elevated blood pressure in the SHR during interference with the functioning of the renin-angiotensin system. Conversely, under conditions of alpha-adrenoceptor blockade, angiotensin II can maintain an elevated blood pressure in the SHR.
Publisher: Informa UK Limited
Date: 1992
DOI: 10.3109/08037059209077670
Abstract: The current experiments were designed to explore the relationship between the renin angiotensin system (RAS) and prostanoid formation in aortic ring preparations from spontaneously hypertensive rats (SHR). A further aim was to examine the mechanisms responsible for the reversal of the impaired acetylcholine (ACh) mediated relaxation induced by chronic administration of the angiotensin converting enzyme inhibitor captopril and the relationship of the ACh response to blood pressure. Rats were administered captopril (100 mg/kg/day) and their blood pressures monitored from 5 to 17 weeks of age. ACh-mediated relaxation was determined in aortic ring preparations from untreated and treated rats, and drug withdrawn rats. The influence of indomethacin, saralasin, SQ29548 and captopril on ACh-mediated responses was determined. It was found that chronic captopril treatment produced a marked suppression of the development of hypertension in the SHR. After the withdrawal of the drug the blood pressure remained significantly lower than in untreated animals for 4 weeks. ACh relaxation was impaired in SHR ring segments this was reversed with captopril treatment and returned to the impaired state upon withdrawal of the drug. In vitro inhibition of the RAS did not significantly influence ACh relaxation. In contrast, impairment of the prostanoid system in vitro reversed the impaired relaxation. The results suggest that the influence of captopril on enhancing ACh relaxation in the SHR does not involve an acute interaction of local angiotensin II synthesis with prostanoid mechanisms. Importantly, the results highlight a dissociation between the impaired ACh relaxation and elevated blood pressure in the SHR.
Publisher: Wiley
Date: 30-10-2016
DOI: 10.1111/BCP.12785
Publisher: Wiley
Date: 03-1998
DOI: 10.1111/J.1440-1681.1998.T01-13-.X
Abstract: 1. 5‐Hydroxytryptamine (5‐HT) exerts both contractile and relaxant effects in the marmoset isolated aorta, actions that are unaffected by the 5‐HT 2 antagonist ketanserin. The aim of the present study was to define the receptors mediating the contractile activity of 5‐HT in the marmoset aorta. 2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A 2 agonist U44069 in order to lify the responses or (ii) exposed to N ω ‐nitro‐ L ‐arginine (100 μmol/L) plus LY 53857 (0.1 μmol/L a 5‐HT 2 receptor antagonist shown previously to inhibit relaxation). The effect of 5‐HT on adenosine 3′,5′‐cyclic monophosphate (cAMP) formation was also investigated. 3. The effects of agonists and antagonists comprised: (i) agonist potencies in the order 5‐carboxamidotryptamine 5‐HT sumatriptan 8‐hydroxy‐2‐(di‐ n ‐propylamino)tetralin (ii) inhibition of contractile action of 5‐HT by the 5‐HT 1D antagonist GR 127935 (iii) a contractile response to methysergide (iv) a lack of effect of tropisetron, an antagonist of 5‐HT 3 and 5‐HT 4 receptors and (v) inhibition of forskolin‐stimulated cAMP formation by 5‐HT (in the presence of LY 53857), indicative of negative coupling to adenylate cyclase. 4. The above effects fulfil the criteria for a 5‐HT 1 ‐like receptor. In view of the previous finding that this contractile response is insensitive to ketanserin, it is concluded that the contractile effects of 5‐HT in the marmoset aorta are mediated exclusively by a 5‐HT 1 ‐like receptor.
Publisher: Elsevier BV
Date: 08-1985
DOI: 10.1016/0160-5402(85)90040-3
Abstract: A precolumn extraction procedure combined with high-performance liquid chromatography with electrochemical detection (HPLC-ECD) has been developed for the identification and quantitation of catechol estrogens, their immediate precursors (estrogens), and their 0-methylated metabolites. These compounds were isolated from Krebs solutions and from perchloric acid tissue extracts or whole tissues by simple solvent extraction prior to quantitation. The optimal conditions for detection by HPLC-ECD were those employing a radial compression module, a C18 Bondapak cartridge, and an isocratic mobile phase of ammonium phosphate (pH 3.0) combined with 30-70% acetonitrile. A biological application of this procedure includes the investigation of the 0-methylation of catechol estrogens by vascular tissue. In the present study, the 0-methylation of 2-hydroxyestradiol by rabbit aorta has been examined. The 0-methylation in segments of thoracic aorta was significantly less than that in abdominal aortic segments, but was reproducible along the length of the thoracic aorta.
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/08037059409101531
Abstract: In the present study, we compared the blood pressure in the SHR-SP and in the spontaneously hypertensive rat (SHR) after dietary administration of fish oil from 4 to 17 weeks of age. The retarding influence of dietary fish oils on the development of hypertension was prominent in the SHR (26 mmHg) and not evident in the SHR-SP (8 mmHg). The enhanced development of blood pressure in both the SHR and the SHR-SP is characterised by an elevated maximum contraction in the mesenteric vascular bed to sympathetic nerve stimulation and to injected noradrenaline. In SHR, but not SHR-SP, this maximum contraction was significantly attenuated by dietary fish oil. Likewise, acetylcholine mediated relaxation of the isolated aorta was enhanced in preparations from the SHR but not the SHR-SP. These physiological changes were also associated with a change in the total n-3 polyunsaturated fatty acids (PUFAs) content in vascular tissue, which were inversely proportional to the prevailing blood pressure values seen in all three strains of rat receiving dietary fish oils. Platelet activated thromboxane production was equally depressed in WKY (Wistar Kyoto), SHR and SHR-SP rats. The results indicate that the blood pressure lowering effect of fish oil when administered during the period of development of hypertension is much greater in the SHR than it is in the SHR-SP. Furthermore the lowering of blood pressure by fish oil administration is related to a restoration of normal vascular contraction and normal vascular relaxation, but not related to a suppression of serum thromboxane production.
Publisher: Elsevier BV
Date: 2001
DOI: 10.1016/S1056-8719(01)00116-2
Abstract: A modified apparatus is described that provides for the simultaneous bathing of the serosa of an intact piece of isolated guinea pig ileum while allowing infusion of the isolated lumen. The comparative compartmental potency of the opioid agonists morphine, casomorphins, and enkephalins to inhibit electrically driven contractions are described in this system. The rank-order potency for serosally applied opioid agonists was (IC(50) values, nM): [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (DAMGO) (15)>[D-Ala(2),D-Leu(5)]-enkephalin (DADLE) (35)> or =morphine (46)> or =[D-Ala(2)]-met-enkephalinamide (55)>[D-Ala(2)]-beta-casomorphin[1--4] amide (122)>beta-casomorphin[1--4] amide (940)>met- and leu-enkephalin (>6000). This contrasted to the rank-order potency for the luminally applied opioid agonists: DADLE (63)>DAMGO (135)>[D-Ala(2)]-met-enkephalinamide=morphine (4700)>[D-Ala(2)]-beta-casomorphin[1--4] amide (29000). beta-Casomorphin[1--4] amide, leu-enkephalin and met-enkephalin are mostly inactive when applied luminally. Furthermore, the opioid antagonists, casoxin 4 and [D-Ala(2)]-casoxin 4, when infused into the lumen, significantly overcame the inhibitory effect of morphine added to the serosal side. This model provides an assay and screening system to differentiate between the effects of chemical agents applied via the blood stream (serosa) or food side (lumen) on quiescent or electrically driven gut activity of the nervous plexi or receptor systems of the ileum.
Publisher: Wiley
Date: 27-10-2021
DOI: 10.1002/PRP2.866
Publisher: Wiley
Date: 06-1997
DOI: 10.1111/J.1440-1681.1997.TB01214.X
Abstract: 1. Na+/H+ antiporter/exchange activity (NHE) in human cheek epithelial cells was assessed in 288 female twins and siblings. The genetic contribution of factors to NHE activity was assessed in 128 matched twin pairs (76 monozygotic (MZ) 52 dizygotic (DZ)). 2. There was a small reduction in NHE with age and body mass index. The significant correlations (+/-their standard error (SE)) within MZ and DZ pairs of twins were 0.54 +/- 0.08 and 0.26 +/- 0.13, respectively, implying that genetic factors accounted for 54% of the variance in age-adjusted NHE. There was no cross-sectional relationship between NHE and measures of blood pressure. Based on within-pair differences, however, there was a weak negative association (r = 0.22 P < 0.05) between mean arterial pressure and NHE. 3. It remains to be determined whether NHE in cheek cells is associated with blood pressure tracking over time in young females.
Publisher: Wiley
Date: 23-06-2020
DOI: 10.1002/PRP2.620
Publisher: Springer Science and Business Media LLC
Date: 30-04-2013
DOI: 10.1038/MP.2013.40
Abstract: Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aβ (extracellular β-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aβ accumulation, therefore, providing a platform for developing a population-based screen.
Publisher: Wiley
Date: 18-11-2021
DOI: 10.1111/BCP.14551
Publisher: S. Karger AG
Date: 1986
DOI: 10.1159/000158656
Abstract: In the present study, we utilized 2 perfused mesenteric vascular bed preparations in an examination of the responses of mesenteric vessels from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. One preparation involved perfusion of the mesenteric vascular bed dissected free from the intestine. The second preparation was essentially similar, with the exception that the intestine and the small arterioles feeding the jejunum were intact. The results suggested that the small vessels offer a significant contribution to the mechanical resistance to perfusion in the mesenteric vasculature and are important in the neurogenic responses of this preparation. In contrast, the arterioles in the arcade supplying the jejunum play only a minor role in the responses of the mesenteric vascular bed to intraluminally injected vasoactive substances. It was found that mesenteric preparations from SHR rats responded more forcefully to intraluminally administered norepinephrine and potassium, regardless of whether the intestine was absent or present. Similarly, the responses of mesenteric preparations to electrical nerve stimulation were greater in preparations from SHR rats, particularly when the intestine was present. It is concluded that the perfused mesenteric vasculature from SHR rats is more responsive to vasoactive substances and nerve stimulation and that this feature is not exclusively dependent upon a contribution to contraction by the arterioles supplying the jejunum.
Publisher: Elsevier BV
Date: 07-1990
Publisher: Springer Science and Business Media LLC
Date: 02-10-2012
DOI: 10.1038/TP.2012.91
Publisher: S. Karger AG
Date: 1977
DOI: 10.1159/000158131
Abstract: When assayed on homogenates of the rabbit ear artery up to 192 h after sympathetic denervation, the activity of monoamine oxidase (MAO) showed a small but significant decrease (maximum 9%). The activity of catechol-O-methyl transferase (COMT) appeared unchanged, although it is possible that the small and variable nature of this enzyme activity compared with that of MAO may have masked a comparable effect of denervation. The maximum decreases in noradrenaline (NA) and adenosine triphosphate (ATP) contents were % at 48 h, and 32% at 96 h after denervation. These results confirm the presence of neuronal as well as extraneuronal MAO, and also the presence of extraneuronal COMT in this artery. The decline in ATP contents after denervation suggest that part of the ATP is neuronal. However, the estimated ratio of NA to neuronal ATP is far in excess of that reported for isolated noradrenaline storage vesicles, suggesting that the major portion of the neuronal ATP was not present in these vesicles.
Publisher: Oxford University Press (OUP)
Date: 09-1979
Publisher: Bentham Science Publishers Ltd.
Date: 05-2009
DOI: 10.2174/138161209788186290
Abstract: Interleukin-6 (IL-6) is a multifunctional pro-inflammatory cytokine that is tightly regulated and expressed at low levels in healthy in iduals. Increased IL-6 expression has been associated with a variety of diseases, including inflammatory conditions such as atherosclerosis and cardiovascular disease (obesity, myocardial infarction and type II diabetes). Cytokines including IL-6 and tumour necrosis factor alpha as well as acute phase proteins such as C-reactive protein (CRP) and fibrinogen are key biochemical risk factors for the development of these disease conditions. IL-6 is the key cytokine responsible for the stimulus of synthesis and secretion of CRP. IL-6 activates cell surface signalling via the assembly of IL-6, the IL-6 receptor (IL-6R) and the signalling receptor gp130. Assembly of the (hexameric) signalling complex of IL-6, IL-6R and gp130 occurs in a sequential manner and therefore this signalling complex lends itself to several potential sites for drug targeting. This review discusses some of the mechanisms of IL-6 signalling on various aspects of cardiovascular biology as well as some recent developments in drug targeting of this complex.
Publisher: Wiley
Date: 09-1978
DOI: 10.1111/J.1476-5381.1978.TB08632.X
Abstract: The concentrations of catecholamines and the activities of dopamine-beta-hydroxylase were measured in blood obtained from decapitated diabetic and aged-matched control rats. The activity of dopamine-beta-hydroxylase in blood from diabetic rats was much greater (5 fold) than that seen for control rats. For both diabetic and control rats, decapitation was accompanied by an increase in levels of adrenaline and noradrenaline with no change in the activity of plasma dopamine-beta-hydroxylase. The results are consistent with a predominantly adrenal origin of catecholamines and extra-adrenal origin of dopamine-beta-hydroxylase. The high activity of dopamine-beta-hydroxylase in diabetes indicates either an increased activity of the sympathetic nervous system or changes in dopamine-beta-hydroxylase turnover.
Publisher: Wiley
Date: 13-01-2022
DOI: 10.1002/PRP2.911
Abstract: Infection of humans with SARS‐CoV‐2 virus causes a disease known colloquially as “COVID‐19” with symptoms ranging from asymptomatic to severe pneumonia. Initial pathology is due to the virus binding to the ACE‐2 protein on endothelial cells lining blood vessels and entering these cells in order to replicate. Viral replication causes oxidative stress due to elevated levels of reactive oxygen species. Many (~60%) of the infected people appear to have eliminated the virus from their body after 28 days and resume normal activity. However, a significant proportion (~40%) experience a variety of symptoms (loss of smell and/or taste, fatigue, cough, aching pain, “brain fog,” insomnia, shortness of breath, and tachycardia) after 12 weeks and are diagnosed with a syndrome named “LONG COVID.” Longitudinal clinical studies in a group of subjects who were infected with SARS‐CoV‐2 have been compared to a non‐infected matched group of subjects. A cohort of infected subjects can be identified by a battery of cytokine markers to have persistent, low level grade of inflammation and often self‐report two or more troubling symptoms. There is no drug that will relieve their symptoms effectively. It is hypothesized that drugs that activate the intracellular transcription factor, nuclear factor erythroid‐derived 2‐like 2 (NRF2) may increase the expression of enzymes to synthesize the intracellular antioxidant, glutathione that will quench free radicals causing oxidative stress. The hormone melatonin has been identified as an activator of NRF2 and a relatively safe chemical for most people to ingest chronically. Thus, it is an option for consideration of re‐purposing studies in “LONG COVID” subjects experiencing insomnia, depression, fatigue, and “brain fog” but not tachycardia. Appropriately designed clinical trials are required to evaluate melatonin.
Publisher: Informa UK Limited
Date: 1995
DOI: 10.3109/08037059509077591
Abstract: The effect of dietary fish oils on development of hypertension and vascular response in vitro were studied in rats and a primate. Dietary fish oils (MaxEPA and an n-3 ethyl ester concentrate of higher EPA and DHA content) were administered to spontaneously hypertensive (SHR), stroke-prone spontaneously hypertensive (SHR-SP) and a backcross of SHR and Wistar Kyoto (SHR/WKY) rats from 4-16 weeks of age. Blood pressure was monitored during the feeding period and vascular responses measured in the aorta and mesenteric vascular bed in vitro. Depending on the strain of rat used and the composition of the fish oil the attenuation in blood pressure was 10-26 mmHg. Fish oils attenuated the response mediated by sympathetic nerve stimulation or intralumenal norepinephrine in the perfused mesenteric vascular bed preparation from the SHR. This attenuation was more pronounced for fish oils enriched with eicosapentaenoic acid and docosahexaenoic acid and was more prominent in the SHR and SHR/WKY backcross than it was in the SHR-SP. Prostanoid synthesis or nitric oxide modulation of alpha-adrenoceptor responses were shown not to be involved in the attenuation of vascular responses produced by fish oil. The maximum contraction of aortic ring preparations in response to norepinephrine (NE) was significantly smaller in SHR than WKY rats fed olive oil and for SHR rats maintained on fish oils the contraction was close to WKY olive oil values. Evidence was obtained also for a modulation of vasoconstrictor responses by dietary fish oils in the perfused mesenteric bed of the marmoset monkey.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2002
DOI: 10.1097/00005344-200212000-00015
Abstract: The current investigation explored the potential age-dependant modulation of abnormal spontaneous constrictions (thromboxane-like) in the spontaneously hypertensive rat (SHR) aorta, observed only after the inhibition of endogenous production of nitric oxide (NO). Aortic rings from SHR and Wistar-Kyoto (WKY) control rats of varying ages (4, 8, 12, and 18 months) were mounted in organ baths, and changes in tension were monitored. Inhibition of NO with Nomega-nitro-L-arginine (NOLA) unmasked a slow contraction, which appeared to be age dependent (p < 0.05). This contraction was found in SHRs of all age groups and in older WKY rats. Denuding the endothelium in young SHRs did not influence the constriction, confirming a nonendothelial cell origin, while in the older groups this led to a 30-40% reduction in contraction. Comparable attenuation of the constrictor response was observed after incubation of endothelium intact rings with superoxide dismutase (100 U/ml) or 3-amino-1,2,4-triazole. Of the residual activity that was unaffected by free radical scavengers or de-endothelialization, 60-70% was sensitive to cyclooxygenase inhibition by indomethacin and/or ibuprofen. The thromboxane (TxA ) receptor antagonist SQ29548 induced a complete reversal of the abnormal constriction. In contrast, thromboxane synthetase inhibition had no effect, ruling out any involvement of TxA in mediating this abnormality. Collectively, these observations support the view that as compared with the normotensive setting, contraction induced by NO inhibition in the SHR develops prematurely and deteriorates more rapidly during the aging process. In aged rats, prostaglandin endoperoxide intermediates PGG /H and endothelium-derived free radicals rather than TxA per se appear to contribute to the NOLA-dependent TxA -like vasoconstriction.
Publisher: Wiley
Date: 04-1977
DOI: 10.1038/ICB.1977.15
Abstract: Three semi-automated procedures are described for the estimation of the catecholamine contents of urine, tissue and plasma s les. The three procedures are based on the fluorometric tri-hydroxyindole assay which has been modified for automatic analysis. These techniques offer several advantages over currently available assays in that they are more convenient, provide for faster analysis rate and give increased sensitivity. The results of the present studies in which the catecholamine contents of urine, tissue and plasma s les were determined using the semi-automated assay provided a range of values which was identical to that obtained using other methods.
Publisher: Oxford University Press (OUP)
Date: 26-11-2020
Abstract: The application of science to human nutrition over the centuries has served societies well. One ex le is the identification of key nutrients to overcome nutritional deficiencies, which has enhanced life expectancy. Enhanced life expectancy, however, is associated with an increased prevalence of chronic disorders related to food and nutrition. Findings of studies indicating that in idual responses to nutrients differ substantially between in iduals make it necessary to re-examine the relationship between nutrition and human health. The emergence of new genomic-based technologies illustrates the complexity and scale of the interactions between nutrition and genetic factors. Epigenetic modifications resulting from interactions of the genetic profile, aging, and lifestyle can influence the time course of chronic disorders and contribute to human variability in response to nutritional interventions. Developing a better understanding of human variability as it applies to human nutrition will involve embracing the approaches and principles of complex science.
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C2FO30111C
Abstract: A proline-rich peptide product prepared from bovine whey protein that was enriched in several hydrophobic amino acids including proline (whey proline-rich peptide, wPRP) was shown to modulate the folding pathway of human amyloid beta peptide 1-42 (Aβ42) into oligomers. Concentration-dependent changes in ThT-binding to Ab42 by wPRP indicated suppression of oligomerisation, that was supported by Transmission Electron Microscopy. Suppression of β-sheet and specifically, anti-parallel β-sheet structures by wPRP was demonstrated by ATR-FTIR spectroscopy, where evidence for capacity of wPRP to dissociate pre-existing β-sheet structures in Aβ42 was also apparent. Suppression of anti-parallel β-sheets of oligomeric Aβ42 was associated with rescue of yeast and SH-SY5Y neuronal cells providing important evidence for the association between anti-parallel β-sheet structure and oligomer toxicity. It was proposed that the interaction of wPRP with Aβ42 interfered with the anti-parallel folding pathway of oligomeric Aβ42 and ultimately produced 'off-pathway' structures of lowered total β-sheet content, with attenuated cellular toxicity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1993
DOI: 10.1097/00005344-199311000-00012
Abstract: Evidence suggests that angiotensin II (AII) can modulate neuroeffector responses in the vasculature of spontaneously hypertensive rats (SHR). Included in this modulation is an action of AII in facilitating release of neurotransmitter from sympathetic nerves by a mechanism involving prejunctional angiotensin receptors. In addition, AII may be a substrate for the carrier processes that operate within sympathetic nerves. Therefore, we examined the influence of AII on the responses to sympathetic nerve stimulation in the isolated perfused mesenteric vascular bed preparation and determined whether AII was incorporated into neuronal tissue in blood vessels. AII (10(-8) M) shifted the frequency-response curves to the left, and this shift was reversed with addition of the AII receptor type 1 (AT1) antagonist losartan (10(-6) M). AII uptake into mesenteric artery, thoracic aorta, kidney, and skeletal muscle was determined in tissues taken from SHR and normotensive Wistar-Kyoto rats (WKY). Additional tissues were taken from animals that had been subjected to chemical sympathectomy with 6-hydroxydopamine (6-OHDA). Although AII accumulation was evident in all tissues examined, in no case was this accumulation diminished by 6-OHDA treatment. Subsequent studies using segments of kidney and skeletal muscle demonstrated that a large proportion of AII accumulation was temperature sensitive and was also sensitive to the metabolic inhibitor 2-4-dinitrophenol (DNP 10(-3) M). The results confirm the role of AII in potentiating the responses to sympathetic nerve stimulation through a process involving AT1 receptors, but this process is not associated with neuronal accumulation of the peptide.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1993
DOI: 10.1097/00005344-199305000-00015
Abstract: There is general agreement that the sympathetic nervous system is involved in the development of hypertension in spontaneously hypertensive rats (SHR). However, in a previous study we established that chronic administration of the selective alpha 1-adrenoceptor antagonist terazosin to SHR failed to prevent this phenomenon. In the present study, we extended that investigation further by examining the effects of another selective alpha 1-antagonist (doxazosin), an alpha 2-adrenoceptor antagonist (yohimbine), and a combination of these agents. Chronic administration of doxazosin and yohimbine produced receptor blockade, as determined by their effect on blood pressure (BP) responses to norepinephrine (NE) and phenylephrine. Chronic administration of either antagonist alone or the two in combination failed to prevent the development of hypertension in SHR, however. These findings suggest that although there may be a need for involvement of the sympathetic nervous system in the development of hypertension in SHR, its influence on this process is not mediated through activation of alpha-adrenoceptors.
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/PRP2.918
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/PRP2.917
Abstract: SARS‐CoV‐2 interacting with its receptor, angiotensin‐converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS‐CoV‐2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole‐body response to maintain tissue perfusion. Tissue and circulating renin‐angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT 1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang‐(1‐7) by the enzyme ACE2. Ang‐(1‐7) has effects that are contrary to Ang II‐AT 1 R mediated effects. Thus, destruction of ACE2 by SARS‐CoV‐2 results in loss of control of the pro‐inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS‐CoV‐2 that is responsible for the pathogenesis of COVID‐19.
Publisher: Wiley
Date: 03-1998
DOI: 10.1111/J.1440-1681.1998.T01-13-.X
Abstract: 1. 5‐Hydroxytryptamine (5‐HT) exerts both contractile and relaxant effects in the marmoset isolated aorta, actions that are unaffected by the 5‐HT 2 antagonist ketanserin. The aim of the present study was to define the receptors mediating the contractile activity of 5‐HT in the marmoset aorta. 2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A 2 agonist U44069 in order to lify the responses or (ii) exposed to N ω ‐nitro‐ L ‐arginine (100 μmol/L) plus LY 53857 (0.1 μmol/L a 5‐HT 2 receptor antagonist shown previously to inhibit relaxation). The effect of 5‐HT on adenosine 3′,5′‐cyclic monophosphate (cAMP) formation was also investigated. 3. The effects of agonists and antagonists comprised: (i) agonist potencies in the order 5‐carboxamidotryptamine 5‐HT sumatriptan 8‐hydroxy‐2‐(di‐ n ‐propylamino)tetralin (ii) inhibition of contractile action of 5‐HT by the 5‐HT 1D antagonist GR 127935 (iii) a contractile response to methysergide (iv) a lack of effect of tropisetron, an antagonist of 5‐HT 3 and 5‐HT 4 receptors and (v) inhibition of forskolin‐stimulated cAMP formation by 5‐HT (in the presence of LY 53857), indicative of negative coupling to adenylate cyclase. 4. The above effects fulfil the criteria for a 5‐HT 1 ‐like receptor. In view of the previous finding that this contractile response is insensitive to ketanserin, it is concluded that the contractile effects of 5‐HT in the marmoset aorta are mediated exclusively by a 5‐HT 1 ‐like receptor.
Publisher: Informa UK Limited
Date: 1988
DOI: 10.3109/10641968809103525
Abstract: In this investigation we describe regulation of the vascular alpha-1 receptor and functional properties of resistance vessels in malignant hypertensive DOCA-salt rats (DOCA-salt). Uninephrectomized control and DOCA-salt rats were maintained for 6 weeks microscopic renal morphology provided an index of vascular injury. Radioligand binding studies indicated a striking increase in the density of mesenteric alpha-1 binding sites in DOCA-salt (542 +/- 44 fm/mg) vs. salt control (206 +/- 4 fm/mg) and water control (223 +31 fm/mg) P less than .01. The affinity of the receptor for the radioligand [125I] (+/-) BE 2254 was reduced in DOCA-salt rats. Electrical nerve stimulation and agonist dose response curves were performed on isolated perfused mesenteric arteries. A singular correlation between increased receptor density and vascular responses in DOCA-salt rats could not be demonstrated. The norepinephrine (NE) content of mesenteric arteries was reduced in DOCA-salt (1001 +/- 32 ng/g) vs. water control (1522 +/- 44 ng/g) and saline control (1538 +/- 30 ng/g) P less than .01. Our results indicate, upregulation of the mesenteric alpha-1 receptor occurs in DOCA-salt rats, however, additional factors participate in the vascular response to adrenergic stimulation in this model.
Publisher: AMPCo
Date: 08-2012
DOI: 10.5694/MJA12.10830
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NUTRES.2016.06.006
Abstract: O(6)-methyl guanine (O(6)MeG) adducts are major toxic, promutagenic, and procarcinogenic adducts involved in colorectal carcinogenesis. Resistant starch and its colonic metabolite butyrate are known to protect against oncogenesis in the colon. In this study, we hypothesized that a dietary intervention that specifically delivers butyrate to the large bowel (notably butyrylated high-amylose maize starch [HAMSB]) would reduce colonic levels of O(6)MeG in rats shortly after exposure to the deoxyribonucleic acid (DNA) alkylating agent azoxymethane (AOM) when compared with a low-amylose maize starch (LAMS). A further objective was to validate an immunohistochemistry (IHC) method for quantifying O(6)MeG against a high-performance liquid chromatography method using fluorescence and diode array detection. Rats were fed either LAMS or HAMSB diets for 4 weeks followed by a single injection of AOM or saline and killed 6 hours later. After AOM exposure, both IHC and high-performance liquid chromatography method using fluorescence and diode array detection measured a substantially increased quantity of DNA adducts in the colon (P<.001). Both techniques demonstrated equally that consumption of HAMSB provided a protective effect by reducing colonic adduct load compared with the LAMS diet (P<.05). In addition, IHC allowed visualization of the O(6)MeG distribution, where adduct load was reduced in the lower third of the crypt compartment in HAMSB-fed rats (P=.036). The apoptotic response to AOM was higher in the HAMSB-fed rats (P=.002). In conclusion, the reduction in O(6)MeG levels and enhancement of the apoptotic response to DNA damage in the colonic epithelium through consumption of HAMSB provide mechanistic insights into how HAMSB protects against colorectal tumorigenesis.
Publisher: Informa UK Limited
Date: 20-11-2017
Publisher: Wiley
Date: 12-2013
DOI: 10.1002/ANA.24040
Abstract: Biomarkers for Alzheimer disease (AD) can detect the disease pathology in asymptomatic subjects and in iduals with mild cognitive impairment (MCI), but their cognitive prognosis remains uncertain. We aimed to determine the prognostic value of β-amyloid imaging, alone and in combination with memory performance, hippoc al atrophy, and apolipoprotein E ε4 status in nondemented, older in iduals. A total of 183 healthy in iduals (age = 72.0 ± 7.26 years) and 87 participants with MCI (age = 73.7 ± 8.27) in the Australian Imaging, Biomarkers, and Lifestyle study of ageing were studied. Clinical reclassification was performed after 3 years, blind to biomarker findings. β-Amyloid imaging was considered positive if the (11) C-Pittsburgh compound B cortical to reference ratio was ≥1.5. Thirteen percent of healthy persons progressed (15 to MCI, 8 to dementia), and 59% of the MCI cohort progressed to probable AD. Multivariate analysis showed β-amyloid imaging as the single variable most strongly associated with progression. Of combinations, subtle memory impairment (Z score = -0.5 to -1.5) with a positive amyloid scan was most strongly associated with progression in healthy in iduals (odds ratio [OR] = 16, 95% confidence interval [CI] = 3.7-68 positive predictive value [PPV] = 50%, 95% CI = 19-81 negative predictive value [NPV] = 94%, 95% CI = 88-98). Almost all amnestic MCI subjects (Z score ≤ -1.5) with a positive amyloid scan developed AD (OR = ∞ PPV = 86%, 95% CI = 72-95 NPV = 100%, 95% CI = 80-100). Hippoc al atrophy and ε4 status did not add further predictive value. Subtle memory impairment with a positive β-amyloid scan identifies healthy in iduals at high risk for MCI or AD. Clearly amnestic patients with a positive amyloid scan have prodromal AD and a poor prognosis for dementia within 3 years.
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/08037059409102282
Abstract: Na+ transport activity was measured in cheek cells from untreated hypertensive subjects and age-matched normotensive controls identified from a blood pressure screening program. Cheek cells were isolated by a simple mouth wash procedure and Na+ transport activity was measured as the proton-dependent uptake of 22Na+ using a rapid filtration assay. The rate of Na+ uptake was about 45% lower in hypertensive subjects and this difference persisted in a follow up study 2 years later involving those subjects who remained untreated for their hypertension. The proton independent Na+ uptake was also reduced by about 46% in the hypertensive group. The increase in the rate of cheek cell Na+ transport with increasing transcellular proton gradient values was also significantly lower in hypertensive subjects. The reduced cheek cell Na+ transport observed in hypertensive subjects may indicate decreased activity of the Na+/H+ antiporter and/or changes in the ion permeability properties of the cheek cell plasma membrane in the hypertensive state. This novel assay provides a biochemically based method for discriminating between normotensive and hypertensive subjects and makes use of tissue which can be obtained in a relatively non-invasive manner.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2011
Publisher: Elsevier BV
Date: 10-2012
Publisher: Wiley
Date: 08-1992
DOI: 10.1111/J.1440-1681.1992.TB00502.X
Abstract: 1. In order to explore the mechanisms responsible for the hypernoradrenergic innervation of the vasculature in the spontaneously hypertensive rat (SHR) the tissue content of nerve growth factor messenger ribonucleic acid (NGFmRNA) was examined. 2. The concentration of NGFmRNA was markedly elevated in mesenteric veins obtained from SHR when compared with the contents of NGFmRNA in veins from Wistar Kyoto rats (WKY). 3. The NGFmRNA content of kidneys was greater in SHR when compared with the levels present in WKY rats for 10- and 43-day-old animals. 4. In contrast to the pattern observed for veins and kidneys, the NGFmRNA content of SHR hearts was smaller than those present in hearts from WKY rats for 2, 10 and 43-day-old animals. 5. The results demonstrate that tissues with enhanced innervation (the kidney and mesenteric vasculature) in SHR are associated with an enhanced expression of NGFmRNA. In contrast, the heart, which does not display an enhanced sympathetic innervation in the SHR, does not have an increased expression of NGFmRNA. 6. It is suggested that in the SHR there is a tight relationship between hypernoradrenergic innervation in the vasculature and gene expression for NGFmRNA.
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/PRP2.922
Abstract: Why a systems analysis view of this pandemic? The current pandemic has inflicted almost unimaginable grief, sorrow, loss, and terror at a global scale. One of the great ironies with the COVID‐19 pandemic, particularly early on, is counter intuitive. The speed at which specialized basic and clinical sciences described the details of the damage to humans in COVID‐19 disease has been impressive. Equally, the development of vaccines in an amazingly short time interval has been extraordinary. However, what has been less well understood has been the fundamental elements that underpin the progression of COVID‐19 in an in idual and in populations. We have used systems analysis approaches with human physiology and pharmacology to explore the fundamental underpinnings of COVID‐19 disease. Pharmacology powerfully captures the thermodynamic characteristics of molecular binding with an exogenous entity such as a virus and its consequences on the living processes well described by human physiology. Thus, we have documented the passage of SARS‐CoV‐2 from infection of a single cell to species jump, to tropism, variant emergence and widespread population infection. During the course of this review, the recurrent observation was the efficiency and simplicity of one critical function of this virus. The lethality of SARS‐CoV‐2 is due primarily to its ability to possess and use a variable surface for binding to a specific human target with high affinity. This binding liberates Gibbs free energy (GFE) such that it satisfies the criteria for thermodynamic spontaneity. Its binding is the prelude to human host cellular entry and replication by the appropriation of host cell constituent molecules that have been produced with a prior energy investment by the host cell. It is also a binding that permits viral tropism to lead to high levels of distribution across populations with newly formed virions. This thermodynamic spontaneity is repeated endlessly as infection of a single host cell spreads to bystander cells, to tissues, to humans in close proximity and then to global populations. The principal antagonism of this process comes from SARS‐CoV‐2 itself, with its relentless changing of its viral surface configuration, associated with the inevitable emergence of variants better configured to resist immune sequestration and importantly with a greater affinity for the host target and higher infectivity. The great value of this physiological and pharmacological perspective is that it reveals the fundamental thermodynamic underpinnings of SARS‐CoV‐2 infection.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2015
DOI: 10.1007/S11060-015-1816-Z
Abstract: Personalized medicine has been helpful for drug development in diseases with single and relatively stable gene mutations. The benefit for complex solid tumours with heterogeneous and changing genetic profiles is less clear. Whether it is efficient to continue erting resources from combined biological and pharmacological approaches to trial new and existing genetic 'targeted therapies' for brain tumours is unknown but of developing concern in resource constrained environments.
Publisher: Elsevier BV
Date: 02-1995
DOI: 10.1016/0024-3205(95)00043-6
Abstract: This study investigated the effects of captopril, hydralazine and losartan on the locomotor activity, tailflick and hot plate latencies in spontaneously hypertensive rats (SHR) and their genetic controls the Wistar-Kyoto rat (WKY). The increased hot plate latencies normally exhibited by the spontaneously hypertensive rat were reduced or abolished by captopril (95 mg/kg/day p.o.) and losartan (18 mg/kg/day p.o.) treatment, but were unaffected by hydralazine (19 mg/kg/day p.o.). There were no observable effects of any of the drugs on tailflick latencies or locomotor activity. The results highlight a potential role for angiotensin II in analgesia that is independent of blood pressure change.
Publisher: Wiley
Date: 06-1992
DOI: 10.1111/J.1440-1681.1992.TB00484.X
Abstract: 1. Blood pressure (BP) declines dramatically in the final week of gestation in the pregnant spontaneously hypertensive rat (SHR). This study investigated the hypothesis that alterations of vascular neuroeffector function in the pregnant SHR and normotensive Wistar-Kyoto (WKY) rat are responsible for this decline. 2. Pregnancy in SHR and WKY rats was associated with a significant drop in BP in the last week of gestation. 3. Responses of the perfused mesenteric vasculature to bolus doses of noradrenaline (NA) and potassium chloride (KCl) were decreased in preparations from SHR rats 4 days before delivery. This decreased responsiveness was absent in preparations from SHR rats 1 day before delivery. Responses of the perfused mesenteric vasculature to sympathetic nerve stimulation were not influenced by pregnancy in the SHR. 4. It is concluded that while there are dynamic changes occurring in neurovascular function just prior to delivery, it is unlikely that they are wholly responsible for the dramatic decline in blood pressure in the SHR rat.
Publisher: Informa UK Limited
Date: 1980
DOI: 10.3109/10641968009038556
Abstract: The levels of norepinephrine (NE), dopamine (DA) and epinephrine (E) in the vasculature of hypertension (DOCA-SALT) and normotensive rats were determined by radioenzymatic assay. Significant decreases in the NE content of the mesenteric artery, renal artery and cardiac tissue from DOCA-Salt treated rats were found. In contrast the NE content of the inferior vena cava, abdominal aorta and mesenteric vein were not significantly decreased in the DOCA-Salt treated rats. There was no evidence of an altered disposition of DA and E in the vasculature of DOCA-Salt treated rats. The results of the study indicate that NE is selectively depleted in the cardiovascular system of this model of experimental hypertension and it is proposed that this property reflects different functional roles of in idual elements of the vasculature in the DOCA-Salt hypertensive rat.
Publisher: Bentham Science Publishers Ltd.
Date: 27-12-2013
Publisher: Elsevier BV
Date: 1985
DOI: 10.1016/0197-0186(85)90171-8
Abstract: The concentrations of histamine reported vary considerably from species to species. The present studies sought to determine if blood s ling techniques were at least in part responsible for this large variability. Since plasma catecholamines are influenced by the stress associated with blood s ling, these biogenic amines also were measured. Finally, we explored the possible existence of a relationship between plasma histamine and plasma catecholamine concentrations. The present study confirms that concentrations of histamine in rat plasma are particularly large and establishes that the manner (e.g. awake, anesthetized) and site (e.g. intravenous, decapitation) of blood removal influence the concentrations obtained. The lowest histamine values were seen in s les taken from blood vessels in anesthetized rats. Blood obtained after decapitation showed increasing concentrations of plasma histamine in sequentially obtained s les. An inverse relationship appeared to exist between plasma histamine and plasma catecholamines (predominantly epinephrine). An inhibitory role of epinephrine upon decapitation-associated histamine release was suggested by the observation that both adrenalectomy and catecholamine depletion (alpha-methyl-para-tyrosine) elevated histamine concentrations. Our studies with propranolol, as well as work by other investigators, establish an inhibitory role of ?-receptor stimulation on the release of histamine. On the other hand, histamine injected into the perfused rat adrenal caused a marked release of adrenomedullary catecholamines. In summary our study suggests the presence of a complex interaction between catecholamines and histamine in the regulation of the release of the in idual amines. Our findings point to the existence of a histamine-adrenal axis in which the release of histamine may facilitate the release of epinephrine which in turn may restrict further release of histamine.
Publisher: Oxford University Press (OUP)
Date: 12-2001
DOI: 10.1016/S0008-6363(01)00406-0
Abstract: The cardiovascular health benefits of longchain n-3 polyunsaturated fatty acids (PUFAs) have been reported to exert at several different cellular control mechanisms. These include, effects on lipoprotein metabolism, haemostatic function, platelet/vessel wall interactions, anti-arrhythmic actions and also inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque. Fish oil feeding has also been found to result in moderate reductions in blood pressure and to modify vascular neuroeffector mechanisms. The majority of such cardiovascular benefits of n-3 PUFAs are likely to be mediated in the vascular wall and at the vascular endothelium level, since this monolayer of cells plays a central role in the regulation and maintenance of cardiovascular homeostasis and function. While these processes include endothelium-derived vasorelaxant and vasoconstrictor compounds, the vascular endothelium also plays host to many receptors, binding proteins, transporters and signalling mechanisms. Accordingly, endothelial dysfunction, which underlies many cardiovascular disease conditions, can trigger acute vascular events including vasospasm, thrombosis or restenosis leading to ischaemia. The longchain n-3 PUFAs have been reported to possess several properties that may positively influence vascular function. These include favourable mediator profiles (nitric oxide, eicosanoids) that influence vascular reactivity, change in vascular tone via actions on selective ion channels, and maintenance of vascular integrity. In addition to direct effects on contractility, n-3 PUFAs may affect vascular function, and the process of atherogenesis, via inhibition of vascular smooth muscle cell proliferation at the gene expression level, and by modifying expression of inflammatory cytokinesis and adhesion molecules. Collectively, these properties are consistent with pleiotropic actions of longchain n-3 PUFAs, and may explain the beneficial cardiovascular protection of this family of fatty acids that have been clearly evident through epidemiological data as well from more recent large-scale clinical trials.
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.EVALPROGPLAN.2011.02.008
Abstract: It is the purpose of this article to discuss the development and application of a logic model in the context of a large scientific research program within the Commonwealth Scientific and Industrial Research Organisation (CSIRO). CSIRO is Australia's national science agency and is a publicly funded part of Australia's innovation system. It conducts mission-driven scientific research focussed on delivering results with relevance and impact for Australia, where impact is defined and measured in economic, environmental and social terms at the national level. The Australian Government has recently signalled an increasing emphasis on performance assessment and evaluation, which in the CSIRO context implies an increasing emphasis on ensuring and demonstrating the impact of its research programs. CSIRO continues to develop and improve its approaches to impact planning and evaluation, including conducting a trial of a program logic approach in the CSIRO Preventative Health National Research Flagship. During the trial, improvements were observed in clarity of the research goals and path to impact, as well as in alignment of science and support function activities with national challenge goals. Further benefits were observed in terms of communication of the goals and expected impact of CSIRO's research programs both within CSIRO and externally. The key lesson learned was that significant value was achieved through the process itself, as well as the outcome. Recommendations based on the CSIRO trial may be of interest to managers of scientific research considering developing similar logic models for their research projects. The CSIRO experience has shown that there are significant benefits to be gained, especially if the project participants have a major role in the process of developing the logic model.
Publisher: Elsevier BV
Date: 10-1991
DOI: 10.1016/0952-3278(91)90194-A
Abstract: An influence of fish oils (rich in eicosapentaenoic acid, EPA) in modulating (a) the development of hypertension in the stroke prone spontaneously hypertensive rat (SHRSP) and (b) vascular neuroeffector mechanisms in the SHRSP was explored. Rats (SHRSP) were placed on a series of diets for a period of 13 weeks from 4 weeks of age. The fatty acid composition of the diets was derived from fish oil, olive oil, safflower oil or beef fat. After 13 weeks, rats fed diets containing fish oil (at a total dietary fat level of either 5% or 15%) had mean blood pressures approximately 20-25 mmHg lower than other SHRSP rats maintained on diets containing either olive oil, safflower oil or beef fat. The dietary schedules providing fish oil depressed the contractile responses mediated by sympathetic nerve stimulation in the mesenteric vascular bed preparation. The results suggest that the n-3 polyunsaturated fatty acids retard the development of hypertension in the SHRSP rat and modulate the contractile responses of blood vessels mediated by sympathetic nerves in the isolated perfused mesenteric vascular bed preparation.
Publisher: Elsevier BV
Date: 1984
DOI: 10.1016/0378-4347(84)80093-6
Abstract: A non-radiochemical procedure has been developed which permits the separation and measurement of isoprenaline (ISO) and the O-methylated metabolite, 3-methoxyisoprenaline (MeOISO). This methodology employs alumina chromatography and toluene solvent extraction to separate the catecholamine, ISO, from the O-methylated derivative, MeOISO. High-performance liquid chromatography with electrochemical detection has been used to quantify these compounds. The biological application of this procedure includes the evaluation of O-methylation of the stereoisomers of ISO by intact tissues.
Publisher: REPO4EU
Date: 12-09-2023
DOI: 10.58647/REXPO.23002
Publisher: Wiley
Date: 06-1987
DOI: 10.1111/J.1476-5381.1987.TB10282.X
Abstract: Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (65 mg kg-1). Rabbits were rendered diabetic by injecting alloxan (100 mg kg-1) into the lateral ear vein. Diabetes was confirmed by a significant elevation of serum glucose in both species 8 weeks after injection. The maximum contraction to noradrenaline (NA), 5-hydroxytryptamine (5-HT) and KCl was markedly diminished in thoracic aortic rings (AR) from diabetic rats with no change in the EC50 of the agonists. There were no differences in the contractile properties of AR from diabetic rabbits to NA, 5-HT or KCl. Diabetes did not alter the responsiveness of AR from the rat to angiotensin II (AII). However, AR from diabetic rabbits displayed a decreased maximal contraction and an increased EC50 to AII. The magnitude of the acetylcholine-induced relaxation to precontracted AR was not different between diabetic and control rats and rabbits. The contractile responses of AR to NA, 5-HT and KCl were depressed in diabetic rats, regardless of the control tissue to which they were compared. The decrease in maximal contraction to NA, 5-HT and KCl seen in diabetic animals was prevented by insulin replacement. The results demonstrated that while both rats and rabbits exhibited a similar degree of hyperglycemia after treatment with a diabetogenic agent, aortic preparations from the rabbit are not affected in the same way as the aorta from the diabetic rat when exposed to NA, 5-HT and KCl. This feature may be related to the marked differences between the extent of sympathetic innervation of the aorta in the rabbit and rat. Furthermore, the decrease in maximal contraction in rat aorta was non-specific with respect to agonists since it could also be demonstrated with KCl. Therefore, it follows that the diabetic state may affect processes responsible for contraction beyond the level of receptor activation.
Publisher: S. Karger AG
Date: 1991
DOI: 10.1159/000158889
Abstract: Morphometric studies conducted on the blood vessels of the spontaneously hypertensive rat have provided evidence that medial hypertrophy is a key characteristic of the vascular change which occurs in hypertension. In the present study, we determined whether 3-methylhistidine (3MH), a post-translationally modified amino acid which is found uniquely in the actin and myosin of muscle, could provide a biochemical marker of such change. Our results indicated that the concentrations of 3MH were selectively elevated in the blood vessels from the spontaneously hypertensive rat, when compared with concentrations in vascular tissues from the Wistar-Kyoto rat. The concentrations of 3MH in non-vascular tissues were similar in the two strains. Chronic captopril treatment prevented the development of hypertension in the spontaneously hypertensive rat and was associated with a reduction of the vascular concentrations of 3MH. We therefore conclude that blood vessel concentrations of 3MH are a useful biochemical index of the changes in vascular smooth muscle contractile protein which occur during the development of hypertension in the spontaneously hypertensive rat.
Publisher: Elsevier BV
Date: 02-1984
DOI: 10.1016/0003-2697(84)90352-X
Abstract: To avoid some of the disadvantages associated with using radiolabeling to investigate adenyl purine content and release from excitable tissues, a reverse-phase high-pressure liquid chromatographic method utilizing fluorescence detection for the measurement of picomole amounts of endogenous ATP and its 6-amino purine analogs has been developed. This procedure has been used to determine the content of adenyl purines in the guinea pig vas deferens and that released from the tissue following stimulation of adrenergic nerves. The total tissue content was measured to be 1.6, 0.76, and 0.10 mumol/g of ATP, ADP, and AMP, respectively. However, adenosine could not be detected. Hypoxia caused a significant decrease in ATP content concomitant with an increase in adenosine content to 0.04 mumol/g. Following transmural electrical stimulation of the guniea pig vas deferens, the release of the following purine compounds was detected: ATP (0.106 nmol/g), ADP (0.242 nmol/g), AMP (0.035 nmol/g), and adenosine (0.454 nmol/g).
Publisher: Elsevier BV
Date: 05-1989
DOI: 10.1016/0160-5402(89)90052-1
Abstract: A novel erometric detection procedure was developed to determine the ability of the catechol, 2-hydroxyestradiol (2OHE2), to diffuse through and be O-methylated during its passage from the lumen to the adventitial surface of the rabbit ear artery. The diffusion and O-methylation of d-norepinephrine (d-NE) also was determined. When arteries were perfused with either 2OHE2 or d-NE (10 microM), the bulk of the material effluxing from the adventitial surface was O-methylated. The vessel wall offered a considerable barrier to the diffusion of both NE and 2OHE2, because the concentrations of NE and 2OHE2 found in the solution perfusing the adventitial surface were as much as 1,000-fold lower than their concentration in the intralumenal perfusion stream. It is concluded that the blood vessel wall offers a significant physical and metabolic barrier to the penetration of unchanged 2OHE2 and NE.
Publisher: Elsevier BV
Date: 03-1998
DOI: 10.1016/S1056-8727(97)00072-X
Abstract: Young adult male Hooded Wistar rats were rendered diabetic by administration of streptozotocin and maintained for 5 weeks on a diet containing either 6% olive oil as the total source of fat (OO diet), or purified gamma-linolenic acid (GLA) at a concentration of 0.5% with the remaining 5.5% provided by olive oil (GLA diet). Rats were treated with the angiotensin converting inhibitor, cilazapril, administered in the drinking water at a dose of 20 mg kg-1 body weight day-1. For the OO diet groups, sciatic nerve conduction velocity (NCV) in diabetic rats was reduced by 32% (p < 0.01) in comparison with nondiabetic (vehicle-treated) rats and 27.5% (p < 0.05) in comparison with diabetic rats treated with cilazapril. Diabetic, cilazapril-treated rats showed no reduction in NCV. For the nondiabetic, diabetic, and diabetic plus cilazapril groups fed GLA, the NCV was not significantly different, indicating that dietary GLA also prevented the deficit in the NCV induced by the diabetic state. Analysis of the sciatic nerve endoneurial phospholipid fatty acids revealed a significant reduction in the proportion of GLA and an elevation in the proportion of linoleic acid in the diabetic groups compared with the nondiabetic groups and this was independent of the cilazapril treatment or the dietary lipid supplement. Sciatic nerve myo-inositol content was unaltered while mannose, fructose, glucose, and sorbitol levels were elevated in the diabetic groups and these changes were independent of the cilazapril treatment or the dietary lipid supplement. These results indicate that in the rat, cilazapril treatment or dietary GLA, at the doses tested, are effective in preventing the deficit in the NCV induced by diabetes.
Publisher: Wiley
Date: 10-2002
DOI: 10.1046/J.1440-6047.11.S.7.10.X
Abstract: Plant-based polyphenolic compounds have been reported to possess cardiovascular health benefits. Several dietary sources, including herbs and spices, fruits and vegetables, and tea and wine, contain an array of biologically active compounds that have been shown to be effective in retarding oxidation of low-density lipoproteins (LDL) and promoting vascular relaxation. In the present study four different plant sources, both edible and non-edible, were evaluated for potential activity. Organic extracts enriched in polyphenols were prepared from palm fronds (Elaesis guineensis) lemongrass (Cymbopogon citrates) papaya shoots (Carica papaya) and green chilli (Capsicum frutescenes) and tested for their ability to prevent in vitro oxidation of LDL, and for potential vascular relaxation actions. Rings of rat thoracic aorta and isolated perfused mesenteric vascular beds were mounted in organ baths, contracted using a half-maximal dose of noradrenaline and exposed to cumulative additions of test extracts. Palm frond extract resulted in considerable relaxation (>75%) in both preparations and was found to be endothelium-dependent as removal of endothelium or inhibition of endogenous nitric oxide (NO) led to a total loss in relaxant activity. Lemongrass extract caused a greater relaxation action in the mesenteric preparation compared to aortic rings, and appears to be mediated via NO-independent and non-prostanoid mechanisms. Of the extracts tested, palm fronds also demonstrated the highest antioxidant capacity, as determined by the ferric reducing activity otential assay, and resulted in a significant delay (P < 0.05) in the oxidation of LDL. Collectively, these preliminary findings lend further support to the potential cardiovascular actions of plant polyphenols and also identify oil palm fronds as containing constituents that promote vascular relaxation via endothelium-dependent mechanisms.
Publisher: Elsevier BV
Date: 04-1996
DOI: 10.1016/0014-2999(95)00861-6
Abstract: Dietary fish oils rich in n-3 polyunsaturated fatty acids can modulate a erse range of factors contributing to cardiovascular disease. This study examined the relative roles of eicosapentaenoic acid (20:5 n-3 EPA) and docosahexaenoic acid (22:6 n-3 DHA) which are the principal n-3 polyunsaturated fatty acids regarded as candidates for cardioprotective actions. At low dietary intakes (0.4-1.1% of energy (%en)), docosahexaenoic acid but not eicosapentaenoic acid inhibited ischaemia-induced cardiac arrhythmias. At intakes of 3.9-10.0%en, docosahexaenoic acid was more effective than eicosapentaenoic acid at retarding hypertension development in spontaneously hypertensive rats (SHR) and inhibiting thromboxane-like vasoconstrictor responses in aortas from SHR. In stroke-prone SHR with established hypertension, docosahexaenoic acid (3.9-10.0%en) retarded the development of salt-loading induced proteinuria but eicosapentaenoic acid alone was ineffective. The results demonstrate that purified n-3 polyunsaturated fatty acids mimic the cardiovascular actions of fish oils and imply that docosahexaenoic acid may be the principal active component conferring cardiovascular protection.
Publisher: Elsevier BV
Date: 1991
DOI: 10.1016/0006-8993(91)90437-Z
Abstract: The objectives of this study were to examine the effects of chronic nerve growth factor (NGF) administration on vascular innervation and blood pressure in neonatal rats. Newborn Wistar-Kyoto (WKY) rats bred from normotensive parents were chronically treated with NGF for 8 weeks. Littermate controls received saline. Sympathetic ganglia of treated animals were greatly enlarged and in the superior cervical ganglion neuronal numbers were increased 200% and nuclear areas by 46%. The catecholamine contents of several sympathetically innervated tissues were determined biochemically and found to be significantly elevated in mesenteric arteries, aorta, ileum, adrenal and salivary glands from treated compared to control animals. The catecholamine concentrations were similar to, or exceeded those of the spontaneously hypertensive rat. Histochemically, an aberrant nerve supply was evident occupying a greater volume of the adventitia of the caudal artery and mesenteric arteries. In addition, nerve fibres could be seen penetrating the vessel wall to emerge within the lumen of mesenteric blood vessels. Analysis of the smooth muscle wall of the caudal artery revealed that a small but significantly hyperplastic response had been induced. Systolic blood pressures of NGF-treated and control animals were taken at one week intervals from 5 to 8 weeks of age utilizing the tail cuff method. The blood pressure of treated animals were within the normotensive range. It is concluded that chronic NGF treatment leads to changes in vascular innervation and muscle thickness that are similar to those seen in hypertensive animals. Furthermore, the results suggest the elevated levels of NGF seen in peripheral tissues of the spontaneously hypertensive rat are likely to be responsible for the hyperinnervation and resulting hyperplastic responses within vascular tissues, but not exclusively responsible for the elevated blood pressure.
Publisher: Elsevier BV
Date: 07-1990
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: Informa UK Limited
Date: 02-2011
DOI: 10.2147/CEG.S16161
Publisher: Elsevier BV
Date: 06-1981
DOI: 10.1016/0006-8993(81)90241-9
Abstract: The laminar distribution of tyrosine hydroxylase activity, dopamine and norepinephrine was determined in the dog olfactory bulb. The levels of tyrosine hydroxylase activity and dopamine were highest in the glomerular layer, whereas norepinephrine appeared to be more uniformly distributed across the layers. A similar distribution was observed within the mouse olfactory bulb. Following deafferentation of the mouse olfactory bulb, the levels of tyrosine hydroxylase activity and dopamine declined, while norepinephrine levels showed a transient increase. Subsequent to regeneration of the olfactory nerve, these levels returned to control values. The levels of tyrosine hydroxylase activity and of dopamine were very low or non-detectable in the olfactory epithelium, which contains the olfactory receptor neuron perikarya. The data obtained indicate that tyrosine hydroxylase activity and dopamine content in the bulb are more tightly coupled to each other than either is to norepinephrine content. Since the two catecholamines are in two different classes of neurons, this implies that the bulk of the tyrosine hydroxylase activity in the bulb is associated with the dopamine-containing neurons. Finally, our data are consistent with a transsynaptic control mechanism of the tyrosine hydroxylase activity and dopamine level in the olfactory bulb.
Publisher: Informa UK Limited
Date: 12-2011
DOI: 10.1080/10408398.2010.490883
Abstract: Colorectal cancer is the second leading cause of cancer death in Australia. Nutrition, particularly intake of vegetables and certain plant components, has been reported to have a major role in cancer risk reduction. Recently, there has been a growing research interest in rosemary, a common household plant grown in many parts of the world. This study aims to review scientific evidence from all studies, published from 1996 to March 2010 that examined the protective effects of rosemary on colorectal cancer and other types of cancer. Literature evidence from animal and cell culture studies demonstrates the anticancer potential of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid. No evidence for other rosemary constituents was found. The reported anticancer properties were found to arise through the molecular changes in the multiple-stage process of cancer development, which are dose related and not tissue or species specific. This is evidenced by the ability of rosemary to suppress the development of tumors in several organs including the colon, breast, liver, stomach, as well as melanoma and leukemia cells. The results suggested that the different molecular targets modulated by rosemary and its active constituents are useful indicators of success in clinical cancer chemo-prevention trials.
Publisher: MDPI AG
Date: 07-02-2023
Abstract: Acute myeloid leukaemia (AML) affects predominantly elderly people and has an incidence of 1% of all cancers and 2% of all cancer deaths. Despite using intensive chemotherapy and allogeneic stem cell transplantation, the treatment options for AML remain open for innovation. Thus, there is a need to explore alternative therapies such as less toxic targeted therapies in AML. Aurora A kinase is a well-established target for the treatment of various cancers, including AML. This kinase plays a pivotal role in the cell- ision cycle, particularly in different stages of mitosis, and is also involved in many other cellular regulatory processes. In a previous study, we demonstrated that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In the current study, we have further explored the selectivity of rilpivirine for Aurora A kinase inhibition by testing this drug against a panel of 429 kinases. Concurrently, we demonstrated that rilpivirine significantly inhibited the proliferation of AML cells in a time- and concentration-dependent manner that was preceded by G2/M cell-cycle arrest leading to the induction of apoptosis. Consistent with its kinase inhibitory role, rilpivirine modulated the expression of critical proteins in the Aurora A kinase-signalling pathway. Importantly, orally administered rilpivirine significantly inhibited tumour growth in an HL-60 xenograft model without showing body weight changes or other clinical signs of toxicity. Furthermore, rilpivirine enhanced the anti-proliferative efficacy of the conventional anti-leukaemic chemotherapeutic agent cytarabine. Collectively, these findings provide the stimulus to explore further the anti-leukaemic activity of the anti-viral drug rilpivirine.
Publisher: Elsevier BV
Date: 04-2001
Publisher: Wiley
Date: 05-03-2012
DOI: 10.1111/J.1742-4658.2012.08524.X
Abstract: The in vitro activity of human recombinant β-secretase (BACE1) was studied using a fluorogenic substrate based on the cleavage site for the enzyme in the Swedish mutation of amyloid precursor protein. The enzyme was inhibited by a control peptide inhibitor with good repeatability. The enzyme preparation comprised a mixture of pro-enzyme or zymogen and mature enzyme whereby the pro-enzyme sequence forms a 'flap' that can obstruct the binding site. 'Open flap' forms of the zymogen and mature enzyme are active, but the 'closed flap' form of the zymogen is inactive. This mixture of enzyme populations permitted apparent stimulation of enzyme activity under particular conditions, presumably due to facilitating flap-opening of the zymogen. As reported for heparin, enzyme activation was stimulated in the presence of low concentrations of Tween 20 and dimethylsulfoxide before becoming inhibited at higher concentrations. Dietary plant extracts either consistently inhibited (e.g. clove, tea, cinammon) or consistently stimulated (e.g. mushroom, parsley, asparagus) BACE1. Common structural features identified by Fourier transform infrared spectroscopy revealed that BACE1 activity could be explained by differential interactions of either small molecule or polymeric species with mature versus zymogen forms of the enzyme, respectively. Further, enzyme activity could be reversed by mixtures of high and low mass species. These results may have implications for the regulation of β-secretase activity in vivo by either endogenous or possibly dietary factors and for a potential role of BACE1 in stimulation of the production of amyloid beta peptide in sporadic Alzheimer's disease.
Publisher: Wiley
Date: 02-1977
DOI: 10.1038/ICB.1977.8
Abstract: A sensitive automated assay was developed for the determination of histamine. The endogenous histamine content of intact rabbit thoracic aorta, and of its separated adventitial and medial layers was determined. The histamine content of the intact aorta was found to be only partially sensitive to compound 48/80. The isolated aorta accumulated labelled histamine against a concentration gradient. The uptake was abolished by cooling to 1 degree, but was unaffected by oxygen lack. The uptake process was sensitive to a variety of agents including extraneuronal catecholamine uptake inhibitors (deoxycorticosterone acetate, normetanephrine) as well as inhibitors of catecholamine and histamine metabolism (tranylcypromine, hydrallazine). The uptake was not affected by amodiaquin, a histamine N-methyl-transferase inhibitor, by the metabolites 1,4-methylhistamine or imidazole acetic acid, by compound 48/80 or by the basic amino acid arginine.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1991
DOI: 10.1097/00004872-199107000-00009
Abstract: The postulated antihypertensive effect of dietary fish oil and the influence of dietary sodium on this effect were evaluated in young stroke-prone spontaneously hypertensive rats (SHRSP) by direct intra-arterial measurement of blood pressure. Weaning rats were fed synthetic diets containing olive oil or eicosapentaenoic acid-enriched fish oil (5% of dry weight) with normal (0.23%) or high (2.8%) sodium content. Catheters were implanted after 3 months for blood pressure measurement under resting conditions and to s le blood for catecholamine determinations. Effects of fish oil on vascular reactivity were assessed in the in situ blood-perfused mesentery. The overall observation, from a series of experiments, was that feeding diets containing 5% fish oil to young SHRSP resulted in a small but consistent suppression of the development of hypertension. This effect could be counteracted, however, by increasing dietary sodium intake. Observations after ganglion blockade indicate that the antihypertensive effect of fish oil is unlikely to result from a reduction in sympathetic vascular tone.
Publisher: Cambridge University Press (CUP)
Date: 08-1998
DOI: 10.1017/S0022029998002891
Abstract: There is considerable interest in the possibility that diet-derived isoflavonoids may help in protection against a number of chronic diseases common in Western society. Based on animal studies, however, concerns have been raised that consumption of isoflavonoids by infants and young children may be undesirable. Clover contains isoflavonoids and therefore may represent, via milk, a source of isoflavonoids in the human diet. In this study the concentrations of daidzein (7, 4′-dihydroxyisoflavone), genistein (5, 7, 4′-trihydroxyisoflavone) and equol (7-hydroxy-(4′-hydroxyphenyl)chroman) were measured using HPLC in cows' milk s les obtained from 76 farms in three Australian states. In addition, concentrations were measured in s les collected from one South Australian factory both before and after pasteurization. Concentrations in all s les were found to be extremely low. The mean daidzein concentration was ng/ml. Mean genistein concentrations ranged from just detectable (∼2 ng/ml) in Victorian s les collected during summer to 20-30 ng/ml in s les from all states collected during spring when isoflavonoid-containing clover is most dominant in pasture. Mean equol concentrations ranged from 45±10 ng/ml in Victorian farm s les collected during summer to 293±52 ng/ml in Western Australian s les collected in spring. The mean concentrations of genistein and equol in post-pasteurization s les collected in spring were approximately double those for s les collected in autumn. Pasteurization had no effect on isoflavonoid concentrations. We conclude that the concentrations of isoflavonoids in Australian cows' milk are low and are therefore unlikely to have any pronounced biological effects in human consumers.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1FO10023H
Abstract: The focus of this study was to investigate Angiotensin Converting Enzyme (ACE) inhibiting activity across 34 teas (Camellia sinensis) produced by 5 different processing methods including green (GT), oolong (OT), white (WT), black (BT) and dark (DT) teas. In vitro ACE inhibitory activity was affected by the tea processing method with IC(50) values for ACE inhibition: green < oolong < white < black < dark teas. Substrate-dependence of the reaction kinetics was studied for GT and BT polyphenolic size fractions either 3 kDa and also Green Tea Polyphenolic Isolate (GTPI), and revealed that enzyme velocity curves fitted allosteric, not Michaelis-Menten, relationships. Inhibition was weakly dependent on substrate concentration for GT fraction >3 kDa and independent of substrate concentration for all other GT and BT size fractions and GTPI. Furthermore, evidence for direct inactivation of ACE by GTPI was demonstrated. Overall, the results suggest that tea polyphenolics exert a mixed mode of in vitro inhibition of ACE, mostly of a kinetically uncompetitive type. The results are discussed in the context of in vivo and epidemiological evidence for regulation of blood pressure by tea consumption.
Publisher: Wiley
Date: 06-1989
DOI: 10.1111/J.1440-1681.1989.TB01584.X
Abstract: 1. Deviation supersensitivity and post-junctional supersensitivity are important determinants in the control of the response of smooth muscle. 2. Post-junctional supersensitivity is a process whereby effector cells have augmented responsiveness as a consequence of an impaired physiological stimulus. Deviation supersensitivity which occurs as a result of inhibition of sites of loss or inactivation of the transmitter substance noradrenaline and its analogues also produces an enhanced response of smooth muscle cell preparations. 3. The enzymes monoamine oxidase and catechol-O-methyl transferase are irreversible site of loss of noradrenaline. Functional impairment of these enzymes results in deviation supersensitivity. 4. The complexities involved in unravelling the contribution of noradrenaline metabolizing enzymes to deviation supersensitivity are highlighted with emphasis upon the pioneering work of Professor de la Lande in this field.
Publisher: American Chemical Society (ACS)
Date: 05-11-2012
DOI: 10.1021/PR3007107
Abstract: Butyrate and its analogues have long been investigated as potential chemotherapeutic agents. Our previous structure-activity relationship studies of butyrate analogues revealed that 4-benzoylbutyrate had comparable in vitro effects to butyrate when used to treat HT29 and HCT116 colorectal cancer cell lines. The aim of this study was to identify potential mechanisms associated with the antitumorigenic effects of 4-benzoylbutyrate. In this study, butyrate, 3-hydroxybutyrate and 4-benzoylbutyrate were also investigated for their effects on histone deacetylase (HDAC) activity and histone H4 acetylation in HT29 and HCT116 cells. The biological effects of these analogues on HT29 cells were further investigated using quantitative proteomics to determine the proteins potentially involved in their apoptotic and antiproliferative effects. Because 3-hydroxybutyrate had minimal to no effect on apoptosis, proliferation or HDAC activity, this analogue was used to identify differentially expressed proteins that were potentially specific to the apoptotic effects of butyrate and/or 4-benzoylbutyrate. Butyrate treatment inhibited HDAC activity and induced H4 acetylation. 4-Benzoylbutyrate inhibited HDAC activity but failed to enhance H4 acetylation. Proteomic analysis revealed 20 proteins whose levels were similarly altered by both butyrate and 4-benzoylbutyrate. Proteins that showed common patterns of differential regulation in the presence of either butyrate or 4-benzoylbutyrate included c-Myc transcriptional targets, proteins involved in ER homeostasis, signal transduction pathways and cell energy metabolism. Although an additional 23 proteins were altered by 4-benzoylbutyrate uniquely, further work is required to understand the mechanisms involved in its apoptotic effects.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2009
DOI: 10.1007/S10522-008-9163-5
Abstract: This review assesses the effectiveness and safety of Chinese herbal medicines (CHM) for Mild Cognitive Impairment (MCI) and Age Associated Memory Impairment (AAMI). Electronic searches of English and Chinese databases and hand searches of Chinese journal holdings were conducted. Randomised controlled trials comparing orally administered CHM with placebo, no intervention or other therapy were considered. Ginkgo biloba was excluded. Ten trials met inclusion criteria. Eight different CHM were investigated. Methodological quality was assessed using the Jadad scale and five studies scored three or above. Two studies compared CHM with placebo and eight with another intervention. This review found an overall benefit on some outcome measures for the eight CHMs involved in the 10 RCTs but methodological and data reporting issues were evident. Meta-analysis of three studies found the effects of the CHMs were at least equivalent to piracetam on Mini-Mental State Examination (MMSE) scores. No severe adverse events were reported.
Publisher: S. Karger AG
Date: 1979
DOI: 10.1159/000158222
Publisher: Wiley
Date: 04-2009
DOI: 10.1002/PTR.2656
Abstract: This systematic review aimed to assess the effectiveness and safety of herbal medicines (HM) for treating dementia. Databases in English and Chinese were searched from their inceptions to February 2007. References in reviews and randomized controlled trials (RCTs) were screened by hand. Trials comparing orally administered HM with placebo, no intervention or other therapy were considered. Trials on Ginkgo biloba and its extracts were excluded to avoid duplication of existing reviews. Pairs of authors independently applied eligibility criteria, extracted data and assessed methodological quality using the Jadad Scale. Thirteen RCTs met the inclusion criteria of three or above on this scale. Six trials compared herbal medicine with placebo, one with no treatment, and the remainder with pharmaceutical intervention. Meta-analyses were performed on common cognitive performance outcome measures. All studies reported HM had significant effects in improving symptoms. In studies that employed active controls, HM was at least as effective as the pharmaceutical intervention. Meta-analyses found HM more effective than no treatment or placebo and at least equivalent to control interventions, although the overall effect was small. No severe adverse events were reported. These trials provide overall positive evidence for the effectiveness and safety of certain HMs for dementia management.
Publisher: Wiley
Date: 12-11-1984
DOI: 10.1046/J.1537-2995.1984.24685066810.X
Abstract: The histamine content in plasma s les obtained from a group of healthy blood donors, from blood stored in citrate‐phosphate‐dextrose supplemented with adenine (CPDA) packs for up 28 days, and from the side arm of a transfusion line was measured by radio‐enzymatic assay. Healthy donors had a mean plasma histamine content of 0.79 ng per ml. Blood stored in CPDA initially showed a similar histamine level (0.69 ng/ml on day 3 of storage), but there was a progressive rise with time, and at 28 days, the level was 20.5 ng per ml. The increase in histamine is best described by a positive exponential and may be explained by a process whereby the plasma histamine level increases the degree of histamine release from blood cells. The histamine levels in the blood infused into patients tended to be higher than those found in the stored units of the same age, if these packs were less than 7 days old. This may have been caused by the unit becoming warmer during transfusion. We speculate that the histamine levels in the older units of stored blood were high enough to cause or augment transfusion reactions and that the storage age of blood may have a bearing on the incidence of transfusion reactions.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2013
DOI: 10.1007/S00394-013-0531-9
Abstract: Chronic inflammatory processes contribute to the pathogenesis of many age-related diseases. In search of anti-inflammatory foods, we have systematically screened a variety of common dietary plants and mushrooms for their anti-inflammatory activity. A selection of 115 s les was prepared by a generic food-compatible processing method involving heating. These products were tested for their anti-inflammatory activity in murine N11 microglia and RAW 264.7 macrophages, using nitric oxide (NO) and tumour necrosis factor-α (TNF-α) as pro-inflammatory readouts. Ten food s les including lime zest, English breakfast tea, honey-brown mushroom, button mushroom, oyster mushroom, cinnamon and cloves inhibited NO production in N11 microglia, with IC50 values below 0.5 mg/ml. The most active s les were onion, oregano and red sweet potato, exhibiting IC50 values below 0.1 mg/ml. When these ten food preparations were retested in RAW 264.7 macrophages, they all inhibited NO production similar to the results obtained in N11 microglia. In addition, English breakfast tea leaves, oyster mushroom, onion, cinnamon and button mushroom preparations suppressed TNF-α production, exhibiting IC50 values below 0.5 mg/ml in RAW 264.7 macrophages. In summary, anti-inflammatory activity in these food s les survived 'cooking'. Provided that in idual bioavailability allows active compounds to reach therapeutic levels in target tissues, these foods may be useful in limiting inflammation in a variety of age-related inflammatory diseases. Furthermore, these foods could be a source for the discovery of novel anti-inflammatory drugs.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2016
Publisher: Wiley
Date: 07-2012
Publisher: Elsevier BV
Date: 02-1983
DOI: 10.1016/0006-2952(83)90539-7
Abstract: Local observations indicate that climate change and shifting disturbance regimes are causing permafrost degradation. However, the occurrence and distribution of permafrost region disturbances (PRDs) remain poorly resolved across the Arctic and Subarctic. Here we quantify the abundance and distribution of three primary PRDs using time-series analysis of 30-m resolution Landsat imagery from 1999 to 2014. Our dataset spans four continental-scale transects in North America and Eurasia, covering ~10% of the permafrost region. Lake area loss (-1.45%) dominated the study domain with enhanced losses occurring at the boundary between discontinuous and continuous permafrost regions. Fires were the most extensive PRD across boreal regions (6.59%), but in tundra regions (0.63%) limited to Alaska. Retrogressive thaw slumps were abundant but highly localized (<10
Publisher: Cambridge University Press (CUP)
Date: 03-06-2022
Publisher: American Medical Association (AMA)
Date: 10-2012
Publisher: Wiley
Date: 10-1995
DOI: 10.1111/J.1440-1681.1995.TB01934.X
Abstract: 1. Human cheek cell Na+/H+ antiporter activity (measured as the rate of proton-dependent 22Na+ uptake) was determined in seven normotensive (NT) and four hypertensive (HT) subjects following preincubation of cheek cells with a low molecular weight fraction isolated from NT saliva together with the ionophore, nigericin. 2. Cheek cells preincubated in this manner exhibited greater Na+/H+ antiporter activity with the mean values being 4.2 nmol Na+.mg protein.5 min for the NT group and 1.7 for the HT group. 3. It is possible that stimulation of Na+ transport is due to cellular accumulation of K+ ions during preincubation which, in the presence of the K+/H+ selective ionophore, nigericin, can cause cellular reacidification promoting further 22Na+ uptake via the Na+/H+ antiporter.
Publisher: Wiley
Date: 26-12-2013
DOI: 10.1016/J.JALZ.2012.10.006
Abstract: Alzheimer's disease (AD) is an epidemic facing the entire world. Increased knowledge gained during the past 25 years indicates that AD falls along a clinical and neuropathological spectrum represented as a continuum that extends from preclinical disease in which there are no symptoms, through early symptomatic phases, and finally to AD dementia. The Alzheimer's research community recognizes that imaging, body fluids, and cognitive biomarkers contribute to enhanced diagnostic confidence for AD. There has also been emerging consensus regarding the use of AD biomarkers in clinical trials. The use of biomarkers in clinical trials and practice is h ered by the lack of standardization. In response to the emerging need for standardization, an international meeting of AD researchers was held in Melbourne, Australia, in March 2012 to bring together key researchers, clinicians, industry, and regulatory stakeholders with the aim of generating consensus on standardization and validation of cognitive, imaging, and fluid biomarkers, as well as lifestyle parameters used in research centers worldwide.
No related grants have been discovered for Richard Head.