Aldo Pietro Maggioni

Graphene Oxide Based Recyclable in Vivo Device for Amperometric Monitoring of Interferon-γ in Inflammatory Mice

Publisher: American Chemical Society (ACS)

Date: 10-09-2018

DOI: 10.1021/ACSAMI.8B13518

Abstract: Cytokine sensing is challenging due to their typically low abundances in physiological conditions. Nanomaterial fabricated interfaces demonstrated unique advantages in ultrasensitive sensing. Here, we demonstrate an erometric sensing device based on graphene oxide (GO) and structure-switching aptamers for long-term detection of cytokines in a living organism. The device incorporates a single layer of GO acting as a signal lifier on glassy carbon electrodes. The hairpin aptamers specific to interferon-γ (IFN-γ), which were loaded with redox probes, are covalently attached to GO to serve as biorecognition moieties. IFN-γ was able to trigger the configuration change of aptamers while releasing the trapped redox probes to introduce the electrochemical signal. This in vivo device was capable of quantitatively and dynamically detecting IFN-γ down to 1.3 pg mL

Gender-specific effects of COVID-19 lockdowns on scientific publishing productivity: Impact and resilience

Publisher: Elsevier BV

Date: 03-2023

DOI: 10.1016/J.SOCSCIMED.2023.115761

“Listening” and “talking” to neurons: Implications of immune activation for pain control and increasing the efficacy of opioids

Publisher: Elsevier BV

Date: 11-2007

DOI: 10.1016/J.BRAINRESREV.2007.06.006

Neuroimmunological complications arising from chemotherapy‐induced gut toxicity and opioid exposure in female dark agouti rats

Publisher: Wiley

Date: 12-09-2021

DOI: 10.1002/JNR.24959

Abstract: Cancer patients may experience symptom clusters, including chemotherapy‐induced (CI) gut toxicity (CIGT) and cognitive impairment. Analgesic selection for pain associated with CIGT is difficult as opioids induce glial reactivity and unwanted side effects. This study quantified central glial reactivity and proinflammatory effects in rats with CIGT using three mechanistically different analgesics. Regional adaptations were indicative of immune‐to‐brain signaling routes. Utilizing a 5‐fluorouracil‐induced GT (5IGT) rat model and analgesic intervention (carprofen (CAR), buprenorphine (BUP), and tramadol (TRAM)), spinal and brain neuroimmune modulation was examined via microglial, astrocyte, and proinflammatory (cluster of differentiation molecule 11b CD11b, glial fibrillary associated protein GFAP, and interleukin‐1 beta IL1β) reactivity marker expression changes by western blot analysis. 5IGT significantly increased thoracic GFAP ( p 0.05) and IL‐1β ( p 0.0001) expression, CAR and BUP ameliorated these effects. BUP and TRAM with 5‐FU synergistically increased hippoc al GFAP expression. CAR administered with 5IGT significantly elevated hippoc al and thoracic CD11b expression levels ( p 0.05). The neuroimmune responses observed in this study suggest activation of peripheral‐to‐central immune signaling pathways. We speculate that the opioid‐induced hippoc al changes inferred a humorally mediated mechanism, whereas thoracic neuroimmune modifications indicated activation of an indirect neural route. Although TRAM ameliorated 5IGT‐intestinal inflammation, this opioid presents complications relating to bodyweight and regional glial dysregulation (neuroinflammation) and may not be optimal in the management of pain associated with 5IGT. The chemotherapy‐induced gut‐derived neuroimmune consequences observed suggest a potential mechanistic contribution to central components of the cancer symptom cluster experience, while the opioid‐related glial changes have implications for optimal pain management in this setting warranting further investigation.

Perineuronal net structure as a non-cellular mechanism of affective state, a scoping review

Publisher: INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols

Date: 20-08-2021

DOI: 10.37766/INPLASY2021.8.0075

Abstract: Is the perineuronal net structure within emotional processing brain regions associated with changes in affective state? The objective of this scoping review is to bring together the literature on human and animal studies which have measured perineuronal net structure in brain regions associated with emotional processing (such as but not limited to amygdala, hippoc us and prefrontal cortex). Perineuronal nets are a specialised form of condensed extracellular matrix that enwrap and protect neurons (Suttkus et al., 2016), regulate synaptic plasticity (Celio and Blumcke, 1994) and ion homeostasis (Morawski et al., 2015). Perineuronal nets are dynamic structures that are influenced by external and internal environmental shifts – for ex le, increasing in intensity and number in response to stressors (Blanco and Conant, 2021) and pharmacological agents (Riga et al., 2017). This review’s objective is to generate a compilation of existing knowledge regarding the structural changes of perineuronal nets in experimental studies that manipulate affective state, including those that alter environmental stressors. The outcomes will inform future research directions by elucidating non-cellular central nervous system mechanisms that underpin positive and negative emotional states. These methods may also be targets for manipulation to manage conditions of depression or promote wellbeing. Population: human and animal Condition: affective state as determined through validated behavioural assessment methods or established biomarkers. This includes both positive and negative affective states. Context: PNN structure, measuringPNNs.

Pregnancy Outcomes in Women After Arterial Switch Operation for Transposition of the Great Arteries: Results From ROPAC (Registry of Pregnancy and Cardiac Disease) of the European Society of Cardiolog

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-01-2021

DOI: 10.1161/JAHA.120.018176

Abstract: In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate.

Gender and survival in patients with heart failure: interactions with diabetes and aetiology. Results from the MAGGIC individual patient meta‐analysis†

Publisher: Wiley

Date: 05-2012

DOI: 10.1093/EURJHF/HFS026

Abstract: The aim of this study was to investigate the relationship between gender and survival of patients with heart failure, using data from both randomized trials and observational studies, and the relative contribution of age, left ventricular systolic function, aetiology, and diabetes to differences in prognosis between men and women. Data from 31 studies (41 949 patients 28 052 men, 13 897 women) from the Meta-Analysis Global Group In Chronic Heart Failure (MAGGIC) in idual patient meta-analysis were used. We performed survival analysis to assess the association of gender with mortality, adjusting for predictors of mortality, including age, reduced or preserved ejection fraction (EF), and ischaemic or non-ischaemic aetiology. Women were older [70.5 ( standard deviation 12.1) vs. 65.6 (standard deviation 11.6) years], more likely to have a history of hypertension (49.9% vs. 40.0%), and less likely to have a history of ischaemic heart disease (46.3% vs. 58.7%) and reduced EF (62.6% vs. 81.6%) compared with men. During 3 years follow-up, 3521 (25%) women and 7232 (26%) men died. After adjustment, male gender was an independent predictor of mortality, and the better prognosis associated with female gender was more marked in patients with heart failure of non-ischaemic, compared with ischaemic, aetiology (P-value for interaction = 0.03) and in patients without, compared with those with, diabetes (P-value for interaction <0.0001). This large, in idual patient data meta-analysis has demonstrated that survival is better for women with heart failure compared with men, irrespective of EF. This survival benefit is slightly more marked in non-ischaemic heart failure but is attenuated by concomitant diabetes.

The obesity paradox in heart failure patients with preserved versus reduced ejection fraction: a meta-analysis of individual patient data

Publisher: Springer Science and Business Media LLC

Date: 31-10-2013

DOI: 10.1038/IJO.2013.203

Abstract: In heart failure (HF), obesity, defined as body mass index (BMI) ≥30 kg m(-2), is paradoxically associated with higher survival rates compared with normal-weight patients (the 'obesity paradox'). We sought to determine if the obesity paradox differed by HF subtype (reduced ejection fraction (HF-REF) versus preserved ejection fraction (HF-PEF)). A sub-analysis of the MAGGIC meta-analysis of patient-level data from 14 HF studies was performed. Subjects were ided into five BMI groups: <22.5, 22.5-24.9 (referent), 25-29.9, 30-34.9 and ≥35 kg m(-2). Cox proportional hazards models adjusted for age, sex, aetiology (ischaemic or non-ischaemic), hypertension, diabetes and baseline blood pressure, stratified by study, were used to examine the independent association between BMI and 3-year total mortality. Analyses were conducted for the overall group and within HF-REF and HF-PEF groups. BMI data were available for 23 967 subjects (mean age, 66.8 years 32% women 46% NYHA Class II 50% Class III) and 5609 (23%) died by 3 years. Obese patients were younger, more likely to receive cardiovascular (CV) drug treatment, and had higher comorbidity burdens. Compared with BMI levels between 22.5 and 24.9 kg m(-2), the adjusted relative hazards for 3-year mortality in subjects with HF-REF were: hazard ratios (HR)=1.31 (95% confidence interval=1.15-1.50) for BMI <22.5, 0.85 (0.76-0.96) for BMI 25.0-29.9, 0.64 (0.55-0.74) for BMI 30.0-34.9 and 0.95 (0.78-1.15) for BMI ≥35. Corresponding adjusted HRs for those with HF-PEF were: 1.12 (95% confidence interval=0.80-1.57) for BMI <22.5, 0.74 (0.56-0.97) for BMI 25.0-29.9, 0.64 (0.46-0.88) for BMI 30.0-34.9 and 0.71 (0.49-1.05) for BMI ≥35. In patients with chronic HF, the obesity paradox was present in both those with reduced and preserved ventricular systolic function. Mortality in both HF subtypes was U-shaped, with a nadir at 30.0-34.9 kg m(-2).

Lack of Effect of Lowering LDL Cholesterol on Cancer: Meta-Analysis of Individual Data from 175,000 People in 27 Randomised Trials of Statin Therapy

Publisher: Public Library of Science (PLoS)

Date: 19-01-2012

DOI: 10.1371/JOURNAL.PONE.0029849

Why is neuroimmunopharmacology crucial for the future of addiction research?

Publisher: Elsevier BV

Date: 2014

DOI: 10.1016/J.NEUROPHARM.2013.05.039

<p>Toll-Like Receptor Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhea</p>

Publisher: Informa UK Limited

Date: 03-2020

DOI: 10.2147/JPR.S219684

TheCYP2B6*6Allele Significantly Alters theN-Demethylation of Ketamine Enantiomers In Vitro

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 02-04-2013

DOI: 10.1124/DMD.113.051631

Abstract: Ketamine is primarily metabolized to norketamine by hepatic CYP2B6 and CYP3A4-mediated N-demethylation. However, the relative contribution from each enzyme remains controversial. The CYP2B6*6 allele is associated with reduced enzyme expression and activity that may lead to interin idual variability in ketamine metabolism. We examined the N-demethylation of in idual ketamine enantiomers using human liver microsomes (HLMs) genotyped for the CYP2B6*6 allele, insect cell-expressed recombinant CYP2B6 and CYP3A4 enzymes, and COS-1 cell-expressed recombinant CYP2B6.1 and CYP2B6.6 protein variant. Effects of CYP-selective inhibitors on norketamine formation were also determined in HLMs. The two-enzyme Michaelis-Menten model best fitted the HLM kinetic data. The Michaelis-Menten constants (K(m)) for the high-affinity enzyme and the low-affinity enzyme were similar to those for the expressed CYP2B6 and CYP3A4, respectively. The intrinsic clearance for both ketamine enantiomers by the high-affinity enzyme in HLMs with CYP2B6*1/*1 genotype were at least 2-fold and 6-fold higher, respectively, than those for CYP2B6*1/*6 genotype and CYP2B6*6/*6 genotype. The V(max) and K(m) values for CYP2B6.1 were approximately 160 and 70% of those for CYP2B6.6, respectively. N,N'N'-triethylenethiophosphoramide (thioTEPA) (CYP2B6 inhibitor, 25 μM) and the monoclonal antibody against CYP2B6 but not troleandomycin (CYP3A4 inhibitor, 25 μM) or the monoclonal antibody against CYP3A4 inhibited ketamine N-demethylation at clinically relevant concentrations. The degree of inhibition was significantly reduced in HLMs with the CYP2B6*6 allele (gene-dose P < 0.05). These results indicate a major role of CYP2B6 in ketamine N-demethylation in vitro and a significant impact of the CYP2B6*6 allele on enzyme-ketamine binding and catalytic activity.

Peripheral Interleukin-1β Levels are Elevated in Chronic Tension-Type Headache Patients

Publisher: Hindawi Limited

Date: 2013

DOI: 10.1155/2013/796161

Abstract: BACKGROUND: Tension-type headache is the most common form of headache and its chronic form, chronic tension-type headache (CTTH), is one of the most difficult to treat. The etiology of CTTH is not well understood, but is believed to be multifactorial and to vary among in iduals. In the present study, the authors sought to identify common mechanisms of CTTH pathology. Empirical studies have implicated various immunomodulatory cytokines as mediators of chronic pain disorders, including CTTH. OBJECTIVES: To determine the role of peripheral cytokines and genetic factors in the development of CTTH. METHODS: A panel of cytokines hypothesized to play a role in the pathogenesis of CTTH was measured using cytometric bead arrays and ELISAs in 56 in iduals with CTTH and 42 healthy control participants between 18 and 65 years of age. RESULTS: Levels of interleukin (IL)-1β were significantly elevated in participants diagnosed with CTTH relative to healthy controls, while IL-18 levels were found to be significantly elevated in men with CTTH. Because the levels of these immune mediators were increased in the apparent absence of injury or infection, the authors sought to determine whether genetic changes were responsible for fluctuations in cytokine levels. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to determine in idual genotypes at key single nucleotide polymorphism positions in the IL-1B gene. No association was observed between CTTH and single nucleotide polymorphisms in the IL-1β gene. CONCLUSIONS: These findings suggest that increases in key proinflammatory cytokine levels are associated with CTTH and the pathology of the disorder involves sterile neurovascular inflammation.

First demonstration of the neuroimmune link in humans using IV Endotoxin and Intradermal Capsaicin in the face and arm

Publisher: Springer Science and Business Media LLC

Date: 02-2013

DOI: 10.1186/1129-2377-14-S1-P221

Lesion development is modulated by the natural estrous cycle and mouse strain in a minimally invasive model of endometriosis

Publisher: Oxford University Press (OUP)

Date: 24-10-2017

DOI: 10.1093/BIOLRE/IOX132

Abstract: Many rodent models of endometriosis are invasive, involving surgery to implant donor endometrial tissue into recipient animals. Moreover, few studies have compared and contrasted lesions between rodent strains and estrous stages without exogenous hormone manipulation. This is despite extensive data demonstrating that genetic and hormonal factors can influence endometriosis progression. Here, we have refined a minimally invasive model of endometriosis using naturally cycling mice (donor and recipient matched for cycle phase) to investigate lesion development in two different strains (C57BL/6 and BALB/c), induced in estrous stages of high and low estrogen (proestrus or estrus, respectively), and with varying amounts of donor endometrial tissue (7.5-40 mg), injected intraperitoneally. The overall probability of developing endometriosis-like lesions was higher in proestrus than estrus, and increased with greater masses of donor tissue. Similarly, the total number of lesions (0-3) increased from 7.5 to 40 mg, and was significantly greater in proestrus C57BL/6 mice but not BALB/cs. The dominant lesion type also differed between mouse strains C57BL/6 mice were more likely to develop dense-type lesions, whereas BALB/c mice developed a greater proportion of cystic type. These data further support a role for estrogen in the development of endometriosis, and that genetic variance can influence the degree and characteristics of lesions. Our minimally invasive model would be beneficial for studies with outcome measurements particularly sensitive to incisional injury, such as pain, or alterations to sex hormones, including fertility.

Toll-like Receptor-4: A New Target for Preterm Labour Pharmacotherapies?

Publisher: Bentham Science Publishers Ltd.

Date: 18-05-2018

DOI: 10.2174/1381612824666180130122450

Abstract: Inflammatory activation, a major driver of preterm birth and subsequent neonatal morbidity, is an attractive pharmacological target for new preterm birth therapeutics. Inflammation elicited by intraamniotic infection is causally associated with preterm birth, particularly in infants delivered ≤34 weeks’ gestation. However, sterile triggers of PTB, including placental ischaemic injury, uterine distention, cervical disease, or imbalance in the immune response, also act through inflammatory mediators released in response to tissue damage. Toll-like Receptors (TLRs) are critical upstream gate-keepers controlling the inflammatory activation that precedes preterm delivery, as well as in normal term labour. In particular, TLR4 is implicated for its capacity to sense and integrate a range of disparate infectious and sterile pro-inflammatory triggers, and so acts as a point-ofconvergence through which a range of infectious and sterile agents can activate and accelerate the parturition cascade. Recent studies point to the TLR4 signalling complex as a tractable target for the inhibition of fetal, placental & intraamniotic inflammatory cytokine production. Moreover, studies on mice show that novel small molecule antagonists of TLR4 signalling are highly effective in preventing preterm birth induced by bacterial mimetic LPS, heat-killed E. coli or the TLR4-dependent pro-inflammatory lipid, Platelet Activating Factor (PAF). In this review, we discuss the role of TLR4 in regulating the timing of birth and the potential utility of TLR4 antagonists as novel therapeutics for preterm delivery.

Lovastatin inhibits Toll-like receptor 4 signaling in microglia by targeting its co-receptor myeloid differentiation protein 2 and attenuates neuropathic pain

Publisher: Elsevier BV

Date: 11-2019

DOI: 10.1016/J.BBI.2019.09.013

Abstract: There is growing interest in drug repositioning to find new therapeutic indications for drugs already approved for use in people. Lovastatin is an FDA approved drug that has been used clinically for over a decade as a lipid-lowering medication. While lovastatin is classically considered to act as a hydroxymethylglutaryl (HMG)-CoA reductase inhibitor, the present series of studies reveal a novel lovastatin effect, that being as a Toll-like receptor 4 (TLR4) antagonist. Lovastatin selectively inhibits lipopolysaccharide (LPS)-induced TLR4-NF-κB activation without affecting signaling by other homologous TLRs. In vitro biophysical binding and cellular thermal shift assay (CETSA) show that lovastatin is recognized by TLR4's coreceptor myeloid differentiation protein 2 (MD-2). This finding is supported by molecular dynamics simulations that lovastatin targets the LPS binding pocket of MD-2 and lovastatin binding stabilizes the MD-2 conformation. In vitro studies of BV-2 microglial cells revealed that lovastatin inhibits multiple effects of LPS, including activation of NFkB mRNA expression of tumor necrosis factor-a, interleukin-6 and cyclo-oxygenase 2 production of nitric oxide and reactive oxygen species as well as phagocytic activity. Furthermore, intrathecal delivery of lovastatin over lumbosacral spinal cord of rats attenuated both neuropathic pain from sciatic nerve injury and expression of the microglial activation marker CD11 in lumbar spinal cord dorsal horn. Given the well-established role of microglia and proinflammatory signaling in neuropathic pain, these data are supportive that lovastatin, as a TLR4 antagonist, may be productively repurposed for treating chronic pain.

Can neuroimmune mechanisms explain the link between ultraviolet light (UV) exposure and addictive behavior?

Publisher: Elsevier BV

Date: 10-2018

DOI: 10.1016/J.BBI.2018.07.008

Abstract: High ultraviolet (UV) light exposure on the skin acts as a reinforcing stimulus, increasing sun-seeking behavior and even addiction-like sun seeking behavior. However, the physiological mechanisms that underlie this process remain to be defined. Here, we propose a novel hypothesis that neuroimmune signaling, arising from inflammatory responses in UV-damaged skin cells, causes potentiated signaling within the cortico-mesolimbic pathway, leading to increased sun-seeking behaviors. This hypothesized UV-induced, skin-to-brain signaling depends upon cell stress signals, termed alarmins, reaching the circulation, thereby triggering the activation of innate immune receptors, such as toll-like receptors (TLRs). This innate immune response is hypothesized to occur both peripherally and centrally, with the downstream signaling from TLR activation affecting both the endogenous opioid system and the mesolimbic dopamine pathway. As both neurotransmitter systems play a key role in the development of addiction behaviors through their actions at key brain regions, such as the nucleus accumbens (NAc), we hypothesize a novel connection between UV-induced inflammation and the activation of pathways that contribute to the development of addiction. This paper is a review of the existing literature to examine the evidence which suggests that chronic sun tanning resembles a behavioral addiction and proposes a novel pathway by which persistent sun-seeking behavior could affect brain neurochemistry in a manner similar to that of repeated drug use.

Toll-like receptors in chronic pain

Publisher: Elsevier BV

Date: 04-2012

DOI: 10.1016/J.EXPNEUROL.2011.09.038

Neuroimmune Interactions and Pain: The Role of Immune and Glial Cells

Publisher: Elsevier

Date: 2007

DOI: 10.1016/B978-012088576-3/50023-X

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 13-07-2011

DOI: 10.1124/PR.110.004135

Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast)

Publisher: Elsevier BV

Date: 02-2009

DOI: 10.1016/J.BBI.2008.09.012

Reduced Response to the Thermal Grill Illusion in Chronic Pain Patients

Publisher: Oxford University Press (OUP)

Date: 04-2014

DOI: 10.1111/PME.12379

Abstract: Sensory illusions may reveal fundamental features of the nervous system. The thermal grill illusion is such a pain illusion, where interlaced warm and cool temperature bars (thermal grill) produce a paradoxical burning sensation. Previous studies have only systematically investigated the thermal grill illusion in pain-free volunteers. The objective of this study was to investigate whether the response to the thermal grill illusion was tolerable in patients with chronic pain and whether the response differed between patients with chronic pain and pain-free volunteers. Sixteen pain-free participants and 18 chronic pain patients (seven not receiving opioids and 11 receiving opioids). The thermal grill response was investigated using a custom-built thermal grill. Heat and cold pain thresholds were also determined. Chronic pain patients reported less intense pain, heat, and unpleasantness to the thermal grill compared with pain-free participants in particular, there was an overall main effect for significantly less heat from the thermal grill compared with pain-free participants (P = 0.016). At the 22/38°C combination, although the majority of pain-free participants experienced the illusion to some degree, the majority of pain patients in both groups did not (median pain score 0). Although perceived heat from the thermal grill was significantly lower in chronic pain patients, both heat and cold pain thresholds did not differ among the three populations. This preliminary data suggest that the thermal grill response may provide insights into pain sensitivity that are not detected by conventional thermal quantitative sensory testing.

Stroke Outcomes in the COMPASS Trial

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 26-02-2019

DOI: 10.1161/CIRCULATIONAHA.118.035864

Abstract: Strokes were significantly reduced by the combination of rivaroxaban plus aspirin in comparison with aspirin in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies). We present detailed analyses of stroke by type, predictors, and antithrombotic effects in key subgroups. Participants had stable coronary artery or peripheral artery disease and were randomly assigned to receive aspirin 100 mg once daily (n=9126), rivaroxaban 5 mg twice daily (n=9117), or rivaroxaban 2.5 mg twice daily plus aspirin (n=9152). Patients who required anticoagulation or had a stroke within 1 month, previous lacunar stroke, or intracerebral hemorrhage were excluded. During a mean follow-up of 23 months, fewer patients had strokes in the rivaroxaban plus aspirin group than in the aspirin group (83 [0.9% per year] versus 142 [1.6% per year] hazard ratio [HR], 0.58 95% CI, 0.44–0.76 P .0001). Ischemic/uncertain strokes were reduced by nearly half (68 [0.7% per year] versus 132 [1.4% per year] HR, 0.51 95% CI, 0.38–0.68 P .0001) by the combination in comparison with aspirin. No significant difference was noted in the occurrence of stroke in the rivaroxaban alone group in comparison with aspirin: annualized rate of 0.7% (HR, 0.82 95% CI, 0.65–1.05). The occurrence of fatal and disabling stroke (modified Rankin Scale, 3–6) was decreased by the combination (32 [0.3% per year] versus 55 [0.6% per year] HR, 0.58 95% CI, 0.37–0.89 P =0.01). Independent predictors of stroke were prior stroke, hypertension, systolic blood pressure at baseline, age, diabetes mellitus, and Asian ethnicity. Prior stroke was the strongest predictor of incident stroke (HR, 3.63 95% CI, 2.65–4.97 P .0001) and was associated with a 3.4% per year rate of stroke recurrence on aspirin. The effect of the combination in comparison with aspirin was consistent across subgroups with high stroke risk, including those with prior stroke. Low-dose rivaroxaban plus aspirin is an important new antithrombotic option for primary and secondary stroke prevention in patients with clinical atherosclerosis. URL: www.clinicaltrials.gov . Unique identifier: NCT01776424.

Recent advances in cytokine detection by immunosensing

Publisher: Elsevier BV

Date: 05-2016

DOI: 10.1016/J.BIOS.2016.01.020

Abstract: The detection of cytokines in body fluids, cells, tissues and organisms continues to attract considerable attention due to the importance of these key cell signaling molecules in biology and medicine. In this review, we describe recent advances in cytokine detection in the course of ongoing pursuit of new analytical approaches for these trace analytes with specific focus on immunosensing. We discuss recent elegant designs of sensing interface with improved performance with respect to sensitivity, selectivity, stability, simplicity, and the absence of s le matrix effects. Various immunosensing approaches based on multifunctional nanomaterials open novel opportunities for ultrasensitive detection of cytokines in body fluids in vitro and in vivo. Methodologies such as suspension arrays also known as bead assays together with optical fiber-based sensors, on their own or in combination with microfluidic devices will continue to have an important role to address the grand challenge of real-time in vivo multiplex cytokine detection.

Enduring Reversal of Neuropathic Pain by a Single Intrathecal Injection of Adenosine 2A Receptor Agonists: A Novel Therapy for Neuropathic Pain

Publisher: Society for Neuroscience

Date: 04-11-2009

DOI: 10.1523/JNEUROSCI.3447-09.2009

Abstract: Previous studies of peripheral immune cells have documented that activation of adenosine 2A receptors (A 2A Rs) decrease proinflammatory cytokine release and increase release of the potent anti-inflammatory cytokine, interleukin-10 (IL-10). Given the growing literature supporting that glial proinflammatory cytokines importantly contribute to neuropathic pain and that IL-10 can suppress such pain, we evaluated the effects of intrathecally administered A 2A R agonists on neuropathic pain using the chronic constriction injury (CCI) model. A single intrathecal injection of the A 2A R agonists 4-(3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9 H -purin-2-yl)prop-2-ynyl)piperidine-1-carboxylic acid methyl ester (ATL313) or 2- p -(2-carboxyethyl)phenethylamino-5′- N -ethylcarboxamido adenosine HCl (CGS21680), 10–14 d after CCI versus sham surgery, produced a long-duration reversal of mechanical allodynia and thermal hyperalgesia for at least 4 weeks. Neither drug altered the nociceptive responses of sham-operated controls. An A 2A R antagonist [ZM241385 (4-(2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-ylamino]ethyl)phenol)] coadministered intrathecally with ATL313 abolished the action of ATL313 in rats with neuropathy-induced allodynia but had no effect on allodynia in the absence of the A 2A R agonist. ATL313 attenuated CCI-induced upregulation of spinal cord activation markers for microglia and astrocytes in the L4–L6 spinal cord segments both 1 and 4 weeks after a single intrathecal ATL313 administration. Neutralizing IL-10 antibodies administered intrathecally transiently abolished the effect of ATL313 on neuropathic pain. In addition, IL-10 mRNA was significantly elevated in the CSF cells collected from the lumbar region. Activation of A 2A Rs after intrathecal administration may be a novel, therapeutic approach for the treatment of neuropathic pain by increasing IL-10 in the immunocompetent cells of the CNS.

The Relationship Between Opioids and Immune Signalling in the Spinal Cord

Publisher: Springer Berlin Heidelberg

Date: 2015

DOI: 10.1007/978-3-662-46450-2_11

Abstract: Opioids are considered the gold standard for the treatment of moderate to severe pain. However, heterogeneity in analgesic efficacy, poor potency and side effects are associated with opioid use, resulting in dose limitations and suboptimal pain management. Traditionally thought to exhibit their analgesic actions via the activation of the neuronal G-protein-coupled opioid receptors, it is now widely accepted that neuronal activity of opioids cannot fully explain the initiation and maintenance of opioid tolerance, hyperalgesia and allodynia. In this review we will highlight the evidence supporting the role of non-neuronal mechanisms in opioid signalling, paying particular attention to the relationship of opioids and immune signalling.

A portable optical fiber probe for in vivo brain temperature measurements

Publisher: SPIE

Date: 24-11-2016

DOI: 10.1117/12.2242831

In vivo veritas: (+)-Naltrexone's actions define translational importance

Publisher: Elsevier BV

Date: 09-2014

DOI: 10.1016/J.TIPS.2014.07.002

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2020

DOI: 10.1161/STROKEAHA.120.029762

Abstract: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4% hazard ratio [95% CI], 0.51 [0.38–0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37–1.60]) Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27–1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. URL: www.clinicaltrials.gov . Unique identifier: NCT01776424.

Fluorescence brightness and photostability of individual copper (I) oxide nanocubes

Publisher: Springer Science and Business Media LLC

Date: 04-12-2017

DOI: 10.1038/S41598-017-17295-0

Abstract: Conventional organic fluorophores lose their ability to fluoresce after repeated exposure to excitation light due to photobleaching. Therefore, research into emerging bright and photostable nanomaterials has become of great interest for a range of applications such as bio-imaging and tracking. Among these emerging fluorophores, metal oxide-based nanomaterials have attracted significant attention as a potential multifunctional material with photocatalytic and angeogenisis abilities in addition to fluorescnce applications. However, most of these applications are highly dependent on size, morphology, and chemo-physical properties of in idual particles. In this manuscript, we present a method to study the intrinsic optical characteristics of in idual copper (I) oxide (Cu 2 O) nanocubes. When excited at 520 nm using only 11 µW excitation power (1.7 W/cm2), in idual nanocubes were observed to emit light with peak wavelengths ~760 nm which is conveniently within the near-infrared 1 (NIR1) biological window where tissue autofluorescence is minimal. Bright and photostable fluorescence was observed with intensities up to 487 K counts/s under constant illumination for at least 2 minutes with a brightness approximately four times higher than the autofluorescence from a fixed cumulus-oocyte complex. With near-IR emission, high fluorescence brightness, and outstanding photostability, Cu 2 O nanocubes are attractive candidates for long-term fluorescent bioimaging applications.

Toll-Like Receptor 4 Is an Essential Upstream Regulator of On-Time Parturition and Perinatal Viability in Mice

Publisher: The Endocrine Society

Date: 07-07-2015

DOI: 10.1210/EN.2015-1089

Abstract: An inflammatory response is instrumental in the physiological process of parturition but the upstream signals initiating inflammation are undefined. Because endogenous ligands for Toll-like receptor 4 (TLR4) are released in late gestation, we hypothesized that on-time labor requires TLR4 signaling, to trigger a cytokine and leukocyte response and accelerate the parturition cascade. In pregnant TLR4-deficient (Tlr4−/−) mice, average gestation length was extended by 13 hours and increased perinatal mortality was seen compared with wild-type controls. Quantification of cytokine and uterine activation gene expression showed that late gestation induction of Il1b, Il6, Il12b, and Tnf expression seen in control placenta and fetal membranes was disrupted in Tlr4−/− mice, and accompanied by a transient delay in expression of uterine activation genes, including prostaglandin F receptor, oxytocin receptor, and connexin-43. Leukocyte populations were altered before birth in TLR4-deficient females, with fewer neutrophils and macrophages in the placenta, and fewer dendritic cells and more regulatory T cells in the myometrium. Administration of TLR4 ligand lipopolysaccharide to pregnant wild-type mice induced cytokine expression and fetal loss, whereas Tlr4−/− pregnancies were protected. The small molecule TLR4 antagonist (+)-naloxone increased mean duration of gestation by 16 hours in wild-type mice. Collectively, these data demonstrate that TLR4 is a key upstream regulator of the inflammatory response acting to drive uterine activation and control the timing of labor. Because causal pathways for term and preterm labor converge with TLR4, interventions to manipulate TLR4 signaling may have therapeutic utility for women at risk of preterm labor, or in postterm pregnancy.

Charles Darwin's impressions of New Zealand and Australia, and insights into his illness and his developing ideas on evolution

Publisher: AMPCo

Date: 12-2009

DOI: 10.5694/J.1326-5377.2009.TB03370.X

Abstract: Charles Darwin visited New Zealand in December 1835, and Australia from January until March 1836, on the return portion of his voyage around the world in HMS Beagle. Despite the shortness of these visits, he retained an interest in these countries throughout his life, maintaining correspondence and receiving many biological specimens. His experiences in these places influenced his thinking on evolution, particularly on the evolution of man. Aspects of his health recorded during this part of the voyage support a new hypothesis for the diagnosis of the illness that Darwin endured for most of his life.

Contemporary real life cardioversion of atrial fibrillation: Results from the multinational RHYTHM-AF study

Publisher: Elsevier BV

Date: 04-2014

DOI: 10.1016/J.IJCARD.2014.01.099

Abstract: Electrical and pharmacological cardioversion (ECV, PCV) are important treatment options for symptomatic patients with recent onset atrial fibrillation (AF). RHYTHM-AF is an international registry of present-day cardioversion providing information that is not currently available on country differences and acute and long-term arrhythmia outcomes of ECV and PCV. 3940 patients were enrolled, of whom 75% underwent CV. All patients were followed for 2 months. There were large variations concerning mode of CV used, ECV being heterogeneous. A choice of PCV drug depended on the clinical patient profile. Sinus rhythm was restored in 89.7% of patients by ECV and in 69.1% after PCV. Among patients not undergoing CV during admission, 34% spontaneously converted to sinus rhythm within 24h. ECV was most successful in patients pretreated with antiarrhythmic drugs (mostly amiodarone). PCV was enhanced by class Ic antiarrhythmic drugs conversion rate on amiodarone was similar to that seen with rate control drugs. Female patients and those with paroxysmal and first detected AF as well as those without previous ECV responded well to PCV. The median duration of hospital stay was 16.2 and 24.0 h for ECV and PCV patients, respectively. There were very few CV-related complications regardless of mode of CV. Chronic maintenance of sinus rhythm was enhanced in patients on chronic antiarrhythmic drugs, beta-blockers or inhibitors of the renin-angiotensin system. Mode of CV varied significantly, but both PCV and ECV were safe and effective. Class Ic drugs were most effective conversion drugs, but amiodarone is used most frequently despite providing merely rate control rather than shorten time to conversion.

Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

Publisher: Elsevier BV

Date: 02-2019

DOI: 10.1016/S0140-6736(18)31942-1

Targeting Toll‐like receptor‐4 to tackle preterm birth and fetal inflammatory injury

Publisher: Wiley

Date: 2020

DOI: 10.1002/CTI2.1121

Evolving Expectations of the Orthopedic Team Physician: Managing the Sidelines and Landmines

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2021

DOI: 10.1249/JSR.0000000000000896

Abstract: The role of orthopedic team physicians has evolved greatly over the past decade having been influenced by advances in sports science and performance, new surgical and biologic technologies, social media, medicolegal liability, marketing, and sexual misconduct cases by some team physicians. The great variety of events and sports that are covered from high school and collegiate to the Olympic and professional levels requires a myriad of skills outside of the traditional medical training curriculum. In the current climate of increasing media scrutiny from a 24-h news cycle it is imperative for orthopedic team physicians, whether operative or nonoperative, to continually adapt to the needs and expectations of athletes who also are patients. This is especially true in the wake of the COVID-19 pandemic. Orthopedic team physicians' responsibilities continue to evolve ensuring their relevance and necessity on the sidelines and in the training room as well as in the operative suite.

Effects of a forest pathogen on habitat selection and quality for the endangered golden‐cheeked warbler

Publisher: Wiley

Date: 27-12-2013

DOI: 10.1002/WSB.386

BrainPhys neuronal medium optimized for imaging and optogenetics in vitro

Publisher: Cold Spring Harbor Laboratory

Date: 03-09-2020

DOI: 10.1101/2020.09.02.276535

Abstract: The capabilities of imaging technologies, fluorescent sensors, and optogenetics tools for cell biology have improved exponentially in the last ten years. At the same time, advances in cellular reprogramming and organoid engineering have quickly expanded the use of human neuronal models in vitro . Altogether this creates an increasing need for tissue culture conditions better adapted to live-cell imaging. Here, we identified multiple caveats of traditional media when used for live imaging and functional assays on neuronal cultures (e.g., phototoxicity, suboptimal fluorescence signals, and unphysiological neuronal activity). To overcome these issues, we developed a new neuromedium, “BrainPhys™ Imaging”, in which we adjusted fluorescent and phototoxic compounds. The new medium is based on the formulation of the original BrainPhys medium, which we designed to better support the neuronal activity of human neurons in vitro 1 . We tested the new imaging-optimized formulation on human neurons cultured in monolayers or organoids, and rat primary neurons. BrainPhys Imaging enhanced fluorescence signals and reduced phototoxicity throughout the entire light spectrum. Importantly, consistent with standard BrainPhys, we showed that the new imaging medium optimally supports the electrical and synaptic activity of midbrain and human cortical neurons in culture. We also benchmarked the capacity of the new medium for functional calcium imaging and optogenetic control of human neurons. Altogether, our study shows that the new BrainPhys Imaging improves the quality of a wide range of fluorescence imaging applications with live neurons in vitro while supporting cell viability and neuronal functions.

Artemisinin inhibits TLR4 signaling by targeting co‐receptor MD2 in microglial BV‐2 cells and prevents lipopolysaccharide‐induced blood–brain barrier leakage in mice

Publisher: Wiley

Date: 02-02-2021

DOI: 10.1111/JNC.15302

Abstract: Artemisinin and its derivatives have been the frontline drugs for treating malaria. In addition to the antiparasitic effect, accumulating evidence shows that artemisinins can alleviate neuroinflammatory responses in the central nervous system (CNS). However, the precise mechanisms underlying their anti‐neuroinflammatory effects are unclear. Herein we attempted to delineate the molecule target of artemisinin in microglia. In vitro protein intrinsic fluorescence titrations and saturation transfer difference (STD)‐NMR showed the direct binding of artemisinin to Toll‐like receptor TLR4 co‐receptor MD2. Cellular thermal shift assay (CETSA) showed that artemisinin binding increased MD2 stability, which implies that artemisinin directly binds to MD2 in the cellular context. Artemisinin bound MD2 showed much less collapse during the molecular dynamic simulations, which supports the increased stability of MD2 upon artemisinin binding. Flow cytometry analysis showed artemisinin inhibited LPS‐induced TLR4 dimerization and endocytosis in microglial BV‐2 cells. Therefore, artemisinin was found to inhibit the TLR4‐JNK signaling axis and block LPS‐induced pro‐inflammatory factors nitric oxide, IL‐1β and TNF‐α in BV‐2 cells. Furthermore, artemisinin restored LPS‐induced decrease of junction proteins ZO‐1, Occludin and Claudin‐5 in primary brain microvessel endothelial cells, and attenuated LPS‐induced blood–brain barrier disruption in mice as assessed by Evans blue. In all, this study unambiguously adds MD2 as a direct binding target of artemisinin in its anti‐neuroinflammatory function. The results also suggest that artemisinin could be repurposed as a potential therapeutic intervention for inflammatory CNS diseases. image

The Importance of Knowing You are Sick: Biophotonics For The 'Other' Brain

Publisher: OSA

Date: 2017

DOI: 10.1364/CLEO_SI.2017.SM3C.1

Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.BBI.2013.01.005

Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis

Publisher: Oxford University Press (OUP)

Date: 14-05-2015

DOI: 10.1093/QJMED/HCV087

Risk of Pregnancy in Moderate and Severe Aortic Stenosis

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.JACC.2016.07.750

Abstract: Controversial results on maternal risk and fetal outcome have been reported in women with aortic stenosis (AS). The authors sought to investigate maternal and fetal outcomes in patients with AS in a large cohort. The Registry on Pregnancy and Cardiac Disease (ROPAC) is a global, prospective observational registry of women with structural heart disease, providing a uniquely large study population. Data of women with moderate (peak gradient 36 to 63 mm Hg) and severe AS (peak gradient ≥64 mm Hg) were analyzed. Of 2,966 pregnancies in ROPAC, the authors identified 96 women who had at least moderate AS (34 with severe AS). No deaths were observed during pregnancy and in the first week after delivery. However, 20.8% of women were hospitalized for cardiac reasons during pregnancy. This was significantly more common in severe AS compared with moderate AS (35.3% vs. 12.9% p = 0.02), and reached the highest rate (42.1%) in severe, symptomatic AS. Pregnancy was complicated by heart failure in 6.7% of asymptomatic and 26.3% of symptomatic patients, but could be managed medically, except for 1 patient who was symptomatic before pregnancy and underwent balloon valvotomy. Children of patients with severe AS had a significantly higher percentage of low birth weight (35.0% vs. 6.0% p = 0.006). Mortality in pregnant women with AS, including those with severe AS, appears to be close to zero in the current era. Symptomatic and severe AS does, however, carry a substantial risk of heart failure and is associated with high rates of hospitalization for cardiac reasons, although heart failure can nearly always be managed medically. The results highlight the importance of appropriate pre-conceptional patient evaluation and counseling.

Silk: A bio-derived coating for optical fiber sensing applications

Publisher: Elsevier BV

Date: 05-2020

DOI: 10.1016/J.SNB.2020.127864

Immune‐to‐Brain Communication in Pain: Historical Perspectives, New Directions

Publisher: Wiley

Date: 11-2013

DOI: 10.1002/9781118314814.CH9

Glial TLR4 signaling does not contribute to opioid-induced depression of respiration

Publisher: American Physiological Society

Date: 15-10-2014

DOI: 10.1152/JAPPLPHYSIOL.00534.2014

Abstract: Opioids activate glia in the central nervous system in part by activating the toll-like receptor 4 (TLR4)/myeloid differentiation 2 (MD2) complex. TLR4/MD2-mediated activation of glia by opioids compromises their analgesic actions. Glial activation is also hypothesized as pivotal in opioid-mediated reward and tolerance and as a contributor to opioid-mediated respiratory depression. We tested the contribution of TLR4 to opioid-induced respiratory depression using rhythmically active medullary slices that contain the pre-Bötzinger Complex (preBötC, an important site of respiratory rhythm generation) and adult rats in vivo. Injection with DAMGO (μ-opioid receptor agonist 50 μM) or bath application of DAMGO (500 nM) or fentanyl (1 μM) slowed frequency recorded from XII nerves to 40%, 40%, or 50% of control, respectively. This DAMGO-mediated frequency inhibition was unaffected by preapplication of lipopolysaccharides from Rhodobacter sphaeroides (a TLR4 antagonist, 2,000 ng/ml) or (+)naloxone (1–10 μM, a TLR4-antagonist). Bath application of (−)naloxone (500 nM a TLR4 and μ-opioid antagonist), however, rapidly reversed the opioid-mediated frequency decrease. We also compared the opioid-induced respiratory depression in slices in vitro in the absence and presence of bath-applied minocycline (an inhibitor of microglial activation) and in slices prepared from mice injected (ip) 18 h earlier with minocycline or saline. Minocycline had no effect on respiratory depression in vitro. Finally, the respiratory depression evoked in anesthetized rats by tail vein infusion of fentanyl was unaffected by subsequent injection of (+)naloxone, but completely reversed by (−)naloxone. These data indicate that neither activation of microglia in preBötC nor TLR4/MD2-activation contribute to opioid-induced respiratory depression.

An international perspective on heart failure and left ventricular systolic dysfunction complicating myocardial infarction: the VALIANT registry

Publisher: Oxford University Press (OUP)

Date: 11-2004

DOI: 10.1016/J.EHJ.2004.08.006

Abstract: We analysed the contemporary incidence, outcomes, and predictors of heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) before discharge in patients with acute myocardial infarction (MI). The baseline presence of HF or LVSD, or its development during hospitalisation, increases short- and long-term risk after MI, yet its incidence, predictors, and outcomes have not been well described in a large, international, general MI population. The VALIANT registry included 5573 consecutive MI patients at 84 hospitals in nine countries from 1999 to 2001. A multivariable logistic survival model was constructed using baseline variables to determine the adjusted mortality risk for those with in-hospital HF and/or LVSD. Baseline variables were also tested for associations with in-hospital HF and/or LVSD. Of the 5566 patients analysed, 42% had HF and/or LVSD during hospitalisation. Their in-hospital mortality rate was 13.0% compared with 2.3% for those without HF and/or without LVSD. After adjustment for other baseline risk factors, in-hospital HF and/or LVSD carried a hazard ratio for in-hospital mortality of 4.12 (95% confidence interval: 3.08-5.56). Patients with HF and/or LVSD also had disproportionately higher rates of other cardiovascular events. HF and/or LVSD is common in the general contemporary MI population and precedes 80.3% of all in-hospital deaths after MI. Survivors of early MI-associated HF and/or LVSD have more complications, longer hospitalisations, and are more likely to die during hospitalisation. Although baseline variables can identify MI patients at highest risk for HF and/or LVSD, such patients are less likely to receive indicated procedures and medical therapies.

Exploring neuroinflammation as a potential avenue to improve the clinical efficacy of opioids

Publisher: Informa UK Limited

Date: 11-2012

DOI: 10.1586/ERN.12.125

Abstract: Opioids are an extremely important part of medical practice, and for thousands of years, continued to provide relief from severe acute and chronic pain. Intriguingly, use of opioids activates endogenous counter-regulatory mechanisms resulting in increased sensitivity to noxious stimuli and the requirement for higher doses of opioids to reach an effective level of analgesia. Until recently, research into the counter regulators of opioid-induced analgesia had been focused on the role of neuronal receptors where the beneficial and detrimental actions of opioids were thought to be inseparable. It is now apparent from molecular and rodent data that opioids have non-neuronal, nonclassic, nonstereoselective sites of action. At these newly recognized sites, opioid activity significantly modifies the pharmacodynamics of opioids by eliciting proinflammatory reactivity from immunocompetent cells of the CNS. This review will examine the nonclassic actions of opioids specifically appreciating the actions of the released immune products.

Sensitive Cytokine Assay Based on Optical Fiber Allowing Localized and Spatially Resolved Detection of Interleukin-6

Publisher: No publisher found

DOI: 10.1021/ACSSENSORS.6B00619}

In vivo intrathecal IL-1β quantification in rats

Publisher: Elsevier BV

Date: 08-2020

DOI: 10.1016/J.BBI.2020.04.009

Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia

Publisher: Elsevier BV

Date: 11-2008

DOI: 10.1016/J.BBI.2008.05.004

Clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy: an ESC EORP registry

Publisher: Oxford University Press (OUP)

Date: 25-08-2020

DOI: 10.1093/EURHEARTJ/EHAA455

Abstract: We sought to describe the clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy (PPCM) globally. In 2011, & national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global registry on PPCM, under the auspices of the ESC EURObservational Research Programme. These societies were tasked with identifying centres who could participate in this registry. In low-income countries, e.g. Mozambique or Burkina Faso, where there are no national societies due to a shortage of cardiologists, we identified potential participants through abstracts and publications and encouraged participation into the study. Seven hundred and thirty-nine women were enrolled in 49 countries in Europe (33%), Africa (29%), Asia-Pacific (15%), and the Middle East (22%). Mean age was 31 ± 6 years, mean left ventricular ejection fraction (LVEF) was 31 ± 10%, and 10% had a previous pregnancy complicated by PPCM. Symptom-onset occurred most often within 1 month of delivery (44%). At diagnosis, 67% of patients had severe (NYHA III/IV) symptoms and 67% had a LVEF ≤35%. Fifteen percent received bromocriptine with significant regional variation (Europe 15%, Africa 26%, Asia-Pacific 8%, the Middle East 4%, P & 0.001). Follow-up was available for 598 (81%) women. Six-month mortality was 6% overall, lowest in Europe (4%), and highest in the Middle East (10%). Most deaths were due to heart failure (42%) or sudden (30%). Re-admission for any reason occurred in 10% (with just over half of these for heart failure) and thromboembolic events in 7%. Myocardial recovery (LVEF & 50%) occurred only in 46%, most commonly in Asia-Pacific (62%), and least commonly in the Middle East (25%). Neonatal death occurred in 5% with marked regional variation (Europe 2%, the Middle East 9%). Peripartum cardiomyopathy is a global disease, but clinical presentation and outcomes vary by region. Just under half of women experience myocardial recovery. Peripartum cardiomyopathy is a disease with substantial maternal and neonatal morbidity and mortality.

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

Publisher: Springer Science and Business Media LLC

Date: 13-09-2016

DOI: 10.1038/TP.2016.168

Abstract: In the central nervous system, bidirectional signaling between glial cells and neurons (‘neuroimmune communication’) facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions.

Spinal Glial Adaptations Occur in a Minimally Invasive Mouse Model of Endometriosis: Potential Implications for Lesion Etiology and Persistent Pelvic Pain

Publisher: Springer Science and Business Media LLC

Date: 03-2019

DOI: 10.1177/1933719118773405

Abstract: Glial adaptations within the central nervous system are well known to modulate central sensitization and pain. Recently, it has been suggested that activity of glial-related proinflammatory cytokines may potentiate peripheral inflammation, via central neurogenic processes. However, a role for altered glial function has not yet been investigated in the context of endometriosis, a chronic inflammatory condition in women associated with peripheral lesions, often manifesting with persistent pelvic pain. Using a minimally invasive mouse model of endometriosis, we investigated associations between peripheral endometriosis-like lesions and adaptations in central glial reactivity. Spinal cords (T13-S1) from female C57BL/6 mice with endometriosis-like lesions (ENDO) were imaged via fluorescent immunohistochemistry for the expression of glial fibrillary acidic protein (GFAP astrocytes) and CD11b (microglia) in the dorsal horn (n = 5). Heightened variability ( P = .02) as well as an overall increase ( P = .04) in the mean area of GFAP immunoreactivity was found in ENDO versus saline-injected control animals. Interestingly, spinal levels showing the greatest alterations in GFAP immunoreactivity appeared to correlate with the spatial location of lesions within the abdominopelvic cavity. A subtle but significant increase in the mean area of CD11b immunostaining was also observed in ENDO mice compared to controls ( P = .02). This is the first study to describe adaptations in nonneuronal, immune-like cells of the central nervous system attributed to the presence of endometriosis-like lesions.

Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial

Publisher: Elsevier BV

Date: 2018

DOI: 10.1016/S0140-6736(17)32458-3

Amitriptyline pharmacologically preconditions rat hearts against cardiac ischemic–reperfusion injury

Publisher: Elsevier BV

Date: 07-2015

DOI: 10.1016/J.IJCARD.2015.04.120

Abstract: Amitriptyline (AMY) is a tricyclic anti-depressant that has recently been shown to have anti-inflammatory properties. We investigated whether AMY is cardioprotective against reperfusion injury in ex-vivo rat hearts. Thirty adult Sprague-Dawley rat hearts were perfused ex-vivo in a Langendorff apparatus. All hearts except SHAM (n = 6, perfused for 110 min.) received 30 min no-flow ischemia followed by 40 min reperfusion (I-R). One group (n = 6) was untreated before I-R (non-preconditioned NPC), another non-preconditioned group was perfused with 10 μM amitriptyline for 30 min before I-R (NPC-AMY, n = 6). One group was preconditioned with 3 × 5-minute periods of ischemia before I-R (PC, n = 6) and a fifth group was preconditioned in the presence of 10 μM amitriptyline (PC-AMY, n = 6). p38 phosphorylation and HMGB1 levels were quantified using Western blots. Data was analysed using multiway ANOVAs with Tukey HSD and linear regression models with Sobel mediator tests. NPC hearts recovered poorly (LVDP recovered to 26.5 ± 10.5% of pre-ischemic values, compared to PC hearts (82.8 ± 14.9%: P < 0.05)). PC-AMY (69.9 ± 6.16%) and NPC-AMY (90.3 ± 10.0%) groups both recovered well (P < 0.05). The Sobel mediator test suggested that p38 activity may be indirectly involved in the amitriptyline induced cardioprotection (P < 0.05). HMGB1 was lower in amitriptyline treated hearts compared to the non-preconditioned hearts (P < 0.05) but the multiway ANOVA test suggests that HMGB1 was not involved in amitriptyline induced protection. Amitriptyline at 10 μM protects hearts against ischemic-reperfusion injury which may be partially mediated through p38 phosphorylation.

Considering Precision and Utility When we Talk About Pain. Comment on Cohen et al

Publisher: Elsevier BV

Date: 2023

DOI: 10.1016/J.JPAIN.2022.05.010

Global cardiac risk assessment in the Registry Of Pregnancy And Cardiac disease: results of a registry from the European Society of Cardiology

Publisher: Wiley

Date: 22-03-2016

DOI: 10.1002/EJHF.501

Abstract: To validate the modified World Health Organization (mWHO) risk classification in advanced and emerging countries, and to identify additional risk factors for cardiac events during pregnancy. The ongoing prospective worldwide Registry Of Pregnancy And Cardiac disease (ROPAC) included 2742 pregnant women (mean age ± standard deviation, 29.2 ± 5.5 years) with established cardiac disease: 1827 from advanced countries and 915 from emerging countries. In patients from advanced countries, congenital heart disease was the most prevalent diagnosis (70%) while in emerging countries valvular heart disease was more common (55%). A cardiac event occurred in 566 patients (20.6%) during pregnancy: 234 (12.8%) in advanced countries and 332 (36.3%) in emerging countries. The mWHO classification had a moderate performance to discriminate between women with and without cardiac events (c-statistic 0.711 and 95% confidence interval (CI) 0.686-0.735). However, its performance in advanced countries (0.726) was better than in emerging countries (0.633). The best performance was found in patients with acquired heart disease from developed countries (0.712). Pre-pregnancy signs of heart failure and, in advanced countries, atrial fibrillation and no previous cardiac intervention added prognostic value to the mWHO classification, with a c-statistic of 0.751 (95% CI 0.715-0.786) in advanced countries and of 0.724 (95% CI 0.691-0.758) in emerging countries. The mWHO risk classification is a useful tool for predicting cardiac events during pregnancy in women with established cardiac disease in advanced countries, but seems less effective in emerging countries. Data on pre-pregnancy cardiac condition including signs of heart failure and atrial fibrillation, may help to improve preconception counselling in advanced and emerging countries.

Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

Publisher: Hindawi Limited

Date: 2007

DOI: 10.1100/TSW.2007.230

Abstract: This review will introduce the concept of toll-like receptor (TLR)–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (˗)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use.

The effects of a single exposure to uncontrollable stress on the subsequent conditioned place preference responses to oxycodone, cocaine, and ethanol in rats

Publisher: Springer Science and Business Media LLC

Date: 09-01-2007

DOI: 10.1007/S00213-006-0678-7

Abstract: Acute stress has been shown to facilitate the rewarding effects of a number of commonly abused drugs, although the stressor typically must be administered either immediately before or during drug administration and often in the same environment. We have previously reported that a single session of an uncontrollable (inescapable tailshock, IS), but not controllable (escapable tailshock, ES), stressor can enhance the conditioned place preference (CPP) response to morphine, even when stressor and drug administration are separated temporally and spatially. However, this persistent, trans-situational enhancement did not occur to hetamine CPP. The following experiments were conducted to determine whether the long-term effects of IS on drug reward are specific to opioids. Adult, male Sprague-Dawley rats were exposed to a single session of IS or remained in their home cages (HC). Twenty-four hours later, using an unbiased procedure, CPP conditioning was conducted with either oxycodone (0, 2, or 5 mg/kg, sc), cocaine (0, 1, 5, or 10 mg/kg, ip), or ethanol (0.3, 1, or 2 g/kg, ip). Another group of rats were exposed to IS, ES, or HC treatment and conditioned with oxycodone (5 mg/kg, sc) 24 h later. IS enhanced the subsequent CPP response to oxycodone, but not cocaine or ethanol. This enhancement was dependent on the controllability of the stressor, as ES did not affect oxycodone CPP. These results indicate that the long-term, trans-situational enhancing effect of uncontrollable stress on drug reward is specific to opioids.

Corticosterone Preexposure Increases NF-κB Translocation and Sensitizes IL-1β Responses in BV2 Microglia-Like Cells

Publisher: Frontiers Media SA

Date: 22-01-2018

DOI: 10.3389/FIMMU.2018.00003

Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists

Publisher: American Chemical Society (ACS)

Date: 08-03-2018

DOI: 10.1021/ACS.JCIM.7B00717

Antagonising TLR4-TRIF signalling before or after a low-dose alcohol binge during adolescence prevents alcohol drinking but not seeking behaviour in adulthood

Publisher: Elsevier BV

Date: 2018

DOI: 10.1016/J.NEUROPHARM.2017.09.028

Stimulation of water and calcium dynamics in astrocytes with pulsed infrared light

Publisher: Wiley

Date: 23-03-2020

DOI: 10.1096/FJ.201903049R

One immune system plays many parts: The dynamic role of the immune system in chronic pain and opioid pharmacology

Publisher: Elsevier BV

Date: 05-2023

DOI: 10.1016/J.NEUROPHARM.2023.109459

Sex differences in mechanical allodynia: How can it be preclinically quantified and analyzed?

Publisher: Frontiers Media SA

Date: 2014

DOI: 10.3389/FNBEH.2014.00040

Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids

Publisher: Elsevier BV

Date: 02-2007

DOI: 10.1016/J.BBI.2006.10.011

3,4-Methylenedioxymethamphetamine (MDMA) Induced Hyperthermia-The Role of Pro-Inflammatory Cytokines

Publisher: Bentham Science Publishers Ltd.

Date: 29-03-2011

DOI: 10.2174/1874941001104010048

Minocycline attenuates 3,4-methylenedioxymethamphetamine-induced hyperthermia in the rat brain

Publisher: Elsevier BV

Date: 09-2019

DOI: 10.1016/J.EJPHAR.2019.172495

Abstract: Hyperthermia is most dangerous clinical symptom of acute MDMA administration, and a key factor related to potentially life-threatening MDMA-induced complications. MDMA induces a consistently faster onset of brain hyperthermia when compared to a delayed and moderate hyperthermia in the body, and the most harmful effects of MDMA are related to its modulation of neural functions. The primary focus of this study was to investigate the effects of minocycline, a centrally acting tetracycline derivative on MDMA-induced brain hyperthermia at high ambient temperature. However, we also simultaneously recorded body temperature, heart rate, and locomotor activity changes, allowing us to gain a better understanding of the mechanisms underlying the MDMA-induced hyperthermic response. We also investigated the effects of MDMA at normal ambient temperature to provide further evidence as to the importance of environmental factors on the intensity of MDMA's temperature effects. At normal ambient temperature, MDMA (10 mg/kg, i.p.) induced a significant brain and body hypothermia for the first 90 min following drug administration, and significantly increased heart rate and locomotor activity compared to saline controls. At high ambient temperature however, MDMA (10 mg/kg, i.p.) induced a robust and extended brain and body hyperthermia, as well as significantly increased heart rate and locomotor activity. A 3-day minocycline (50 mg/kg, i.p.) pre-treatment significantly attenuated MDMA-induced increases in brain temperature, body temperature, heart rate, and locomotor activity. Our findings indicate that minocycline is more effective in attenuating the exacerbated MDMA-induced hyperthermic response in the brain compared to the body at high ambient temperature.

Small-Molecule Modulators of Toll-like Receptors

Publisher: American Chemical Society (ACS)

Date: 04-2020

DOI: 10.1021/ACS.ACCOUNTS.9B00631

Therapeutic Strategies to Treat Alcohol-Related Disorders Targeting Central Immune Signaling

Publisher: Springer US

Date: 21-09-2012

DOI: 10.1007/978-1-4614-4729-0_17

Low-dose rivaroxaban plus aspirin in patients with polypharmacy and multimorbidity: an analysis from the COMPASS trial

Publisher: Oxford University Press (OUP)

Date: 30-06-2021

DOI: 10.1093/EHJCVP/PVAB050

Abstract: To analyse whether the benefits and risks of rivaroxaban plus aspirin vary in patients with comorbidities and receiving multiple drugs. In patients with coronary or peripheral artery disease, adding low-dose rivaroxaban to aspirin reduces cardiovascular events and mortality. Polypharmacy and multimorbidity are frequent in such patients. We describe ischaemic events (cardiovascular death, stroke, or myocardial infarction) and major bleeding in participants from the randomized, double-blind COMPASS study by number of cardiovascular medications and concomitant medical conditions. We compared event rates and hazard ratios (HRs) for rivaroxaban plus aspirin vs. aspirin alone by the number of medications and concomitant conditions, and tested for interaction between polypharmacy or multimorbidity and the antithrombotic regimen. The risk of ischaemic events was higher in patients with more concomitant drugs (HR 1.7, 95% confidence interval 1.5–2.1 for & vs. 0–2) and with more comorbidities (HR 2.3, 1.8–2.1 for & vs. 0–1). Multimorbidity, but not polypharmacy, was associated with a higher risk of major bleeding. The relative efficacy, safety, and net clinical benefit of rivaroxaban were not affected by the number of drugs or comorbidities. Patients taking more concomitant medications derived the largest absolute reduction in the net clinical outcome with added rivaroxaban (1.1% vs. 0.4% reduction with & vs. 0–2 cardiovascular drugs, number needed to treat 91 vs. 250). Adding low-dose rivaroxaban to aspirin resulted in benefits irrespective of the number of concomitant drugs or comorbidities. Multiple comorbidities and/or polypharmacy should not dissuade the addition of rivaroxaban to aspirin in otherwise eligible patients.

Constriction of the buccal branch of the facial nerve produces unilateral craniofacial allodynia

Publisher: Elsevier BV

Date: 08-2017

DOI: 10.1016/J.BBI.2016.12.004

RHYTHM-AF: design of an international registry on cardioversion of atrial fibrillation and characteristics of participating centers

Publisher: Springer Science and Business Media LLC

Date: 02-10-2012

DOI: 10.1186/1471-2261-12-85

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

Publisher: Elsevier BV

Date: 2018

DOI: 10.1016/S0140-6736(17)32409-1

The efficacy of (+)-Naltrexone on alcohol preference and seeking behaviour is dependent on light-cycle

Publisher: Elsevier BV

Date: 2018

DOI: 10.1016/J.BBI.2017.08.021

Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174 000 participants in 27 randomised trials

Publisher: Elsevier BV

Date: 04-2015

DOI: 10.1016/S0140-6736(14)61368-4

Biophotonics: the big picture

Publisher: SPIE-Intl Soc Optical Eng

Date: 23-12-2017

DOI: 10.1117/1.JBO.23.2.021103

From the Bottom-Up: Chemotherapy and Gut-Brain Axis Dysregulation

Publisher: Frontiers Media SA

Date: 22-05-2018

DOI: 10.3389/FNBEH.2018.00104

Psychoneuroimmunology goes East: Development of the PNIRS affiliate and its expansion into PNIRS

Publisher: Elsevier BV

Date: 08-2020

DOI: 10.1016/J.BBI.2020.04.026

Predicting survival in heart failure: A risk score based on 39 372 patients from 30 studies

Publisher: Oxford University Press (OUP)

Date: 24-10-2013

DOI: 10.1093/EURHEARTJ/EHS337

Abstract: Using a large international database from multiple cohort studies, the aim is to create a generalizable easily used risk score for mortality in patients with heart failure (HF). The MAGGIC meta-analysis includes in idual data on 39 372 patients with HF, both reduced and preserved left-ventricular ejection fraction (EF), from 30 cohort studies, six of which were clinical trials. 40.2% of patients died during a median follow-up of 2.5 years. Using multivariable piecewise Poisson regression methods with stepwise variable selection, a final model included 13 highly significant independent predictors of mortality in the following order of predictive strength: age, lower EF, NYHA class, serum creatinine, diabetes, not prescribed beta-blocker, lower systolic BP, lower body mass, time since diagnosis, current smoker, chronic obstructive pulmonary disease, male gender, and not prescribed ACE-inhibitor or angiotensin-receptor blockers. In preserved EF, age was more predictive and systolic BP was less predictive of mortality than in reduced EF. Conversion into an easy-to-use integer risk score identified a very marked gradient in risk, with 3-year mortality rates of 10 and 70% in the bottom quintile and top decile of risk, respectively. In patients with HF of both reduced and preserved EF, the influences of readily available predictors of mortality can be quantified in an integer score accessible by an easy-to-use website www.heartfailurerisk.org. The score has the potential for widespread implementation in a clinical setting.

Immune priming and experimental glaucoma: the effect of prior systemic lipopolysaccharide challenge on tissue outcomes after optic nerve injury

Publisher: Wiley

Date: 23-01-2014

DOI: 10.1111/CEO.12289

Abstract: Microglial activation is a prominent feature throughout the optic pathway in experimental glaucoma. Pro-inflammatory microglial activation may contribute to neurodegeneration through the release of pro-inflammatory cytokines and other inflammatory mediators. Systemic administration of lipopolysaccharide stimulates microglia to produce pro-inflammatory cytokines and chemoattractants. A preliminary investigation demonstrated pro-inflammatory microglial activation throughout the optic pathway following systemic lipopolysaccharide challenge. The aim of the current work was to investigate whether microglial priming with lipopolysaccharide would exacerbate optic nerve injury in rats following experimental glaucoma. Adult female Sprague-Dawley rats were ided into lipopolysaccharide treatment (n = 15) and saline treatment groups (n = 15). Microglial priming was induced with a 2.5-mg/kg intraperitoneal injection of lipopolysaccharide control animals received saline. Experimental glaucoma was induced 48 h later in the right eyes of animals by laser photocoagulation of the trabecular meshwork. Animals were sacrificed 9 days after laser treatment. The estimated number of axons per optic nerve was 51 327 ± 3868 (mean ± standard error of the mean) in the lipopolysaccharide group and 54 569 ± 6687 (mean ± standard error of the mean) in the saline group. Optic nerve axon counts were not significantly different between lipopolysaccharide and saline groups (P = 0.67). Systemic lipopolysaccharide challenge had no discernible effect on optic nerve injury in laser-induced experimental glaucoma. These findings do not support the hypothesis that this model of experimental glaucoma involves inflammation and instead suggest that microglial activation may occur secondary to chronic neurodegeneration.

ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation

Publisher: Oxford University Press (OUP)

Date: 24-07-2023

DOI: 10.1093/EURHEARTJ/EHS215

Toll-Like Receptor-4 Antagonist (+)-Naltrexone Protects Against Carbamyl-Platelet Activating Factor (cPAF)-Induced Preterm Labor in Mice

Publisher: Elsevier BV

Date: 05-2020

DOI: 10.1016/J.AJPATH.2020.01.008

Chemical sensing based on silk coated exposed-core fibers

Publisher: SPIE

Date: 30-12-2019

DOI: 10.1117/12.2541320

Measuring and tracking vitamin B12: A review of current methods with a focus on optical spectroscopy

Publisher: No publisher found

DOI: 10.1080/05704928.2016.1229325}

Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction

Publisher: American Medical Association (AMA)

Date: 12-2015

DOI: 10.1001/JAMA.2015.15734

Abstract: Worsening chronic heart failure (HF) is a major public health problem. To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks. The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point. Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969 12 weeks, 7.567 difference, -0.402 geometric means: baseline, 2890 pg/mL 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283 12 weeks, 8.002 difference, -0.280 geometric means: baseline, 3955 pg/mL 12 weeks, 2988 pg/mL) (difference of means, -0.122 90% CI, -0.32 to 0.07 ratio of geometric means, 0.885, 90% CI, 0.73-1.08 P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively. Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF. clinicaltrials.gov Identifier: NCT01951625.

Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae

Publisher: Elsevier BV

Date: 11-2014

DOI: 10.1016/J.NEUROSCIENCE.2014.09.020

Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment

Publisher: SAGE Publications

Date: 09-11-2012

DOI: 10.1177/0333102412467512

Abstract: Patients with chronic headache who consume large amounts of analgesics are often encountered in clinical practice. Excessive intake of analgesics is now considered to be a cause, rather than simply a consequence, of frequent headaches, and as such the diagnosis “medication-overuse headache” (MOH) has been formulated. Despite the prevalence and clinical impact of MOH, the pathophysiology behind this disorder remains unclear and specific mechanism-based treatment options are lacking. Although most acute headache treatments have been alleged to cause MOH, here we conclude from the literature that opioids are a particularly problematic drug class consistently associated with worsening headache. MOH may not be a single entity, as each class of drug implicated may cause MOH via a different mechanism. Recent evidence indicates that chronic opioid administration may exacerbate pain in the long term by activating toll-like receptor-4 on glial cells, resulting in a pro-inflammatory state that manifests clinically as increased pain. Thus, from the available evidence it seems opioid-overuse headache is a phenomenon similar to opioid-induced hyperalgesia, which derives from a cumulative interaction between central sensitisation, due to repeated activation of nociceptive pathways by recurrent headaches, and pain facilitation due to glial activation. Treatment strategies directed at inhibiting glial activation may be of benefit alongside medication withdrawal in the management of MOH.

Science convergence applied to psychoneuroimmunology: The future of measurement and imaging

Publisher: Elsevier BV

Date: 08-2020

DOI: 10.1016/J.BBI.2020.04.029

A novel platform for in vivo detection of cytokine release within discrete brain regions

Publisher: Elsevier BV

Date: 07-2018

DOI: 10.1016/J.BBI.2018.04.011

Abstract: Mounting evidence indicates that cytokines secreted by innate immune cells in the brain play a central role in regulating neural circuits that subserve mood, cognition, and sickness responses. A major impediment to the study of neuroimmune signaling in healthy and disease states is the absence of tools for in vivo detection of cytokine release in the brain. Here we describe the design and application of a cytokine detection device capable of serial monitoring of local cytokine release in discrete brain regions. The immunocapture device consisted of a modified optical fiber labeled with a capture antibody specific for the pro-inflammatory cytokine interleukin-1 beta (IL-1β). Using a sandwich immunoassay method, in vitro data demonstrate that the sensing interface of the modified optical fiber has a linear detection range of 3.9 pg mL

Optical fiber based in-vivo oxidative stress biosensor

Publisher: SPIE

Date: 30-12-2019

DOI: 10.1117/12.2539920

Characterisation of the in vitro modulation of splenocyte proliferation by non-4,5-epoxymorphinan opioids

Publisher: Elsevier BV

Date: 11-2005

DOI: 10.1016/J.INTIMP.2005.05.006

Abstract: Opioids, such as morphine, can directly alter immune function via receptors expressed on immunocompetent cells. However, several studies have questioned the classical opioid nature of this change in immune response. Therefore, it is unclear how opioids that are not from the same structural class as morphine (4,5-epoxymorphinan), will modulate the immune system, if they do not behave in a classical opioid manner. Therefore, the aim of this study was to investigate the in vitro modulatory effects of a range of non-4,5-epoxymorphinan opioids on splenocyte proliferation and compare the response characteristics to their central opioid characteristics. The modulation of concanavalin A stimulated mouse splenocyte proliferation by non-4,5-epoxymorphinan opioids resulted in three types of responses: an inhibitory concentration-response curve (e.g. methadone, inhibitory EC(50)=79.4 microM), an inverted bell shaped curve (e.g. fentanyl, inhibitory EC(50)=0.06 microM) and an induction concentration response curve (e.g. nor-binaltorphimine, induction EC(50)=0.16 microM). Non-stereoselectivity, naloxone-insensitivity, naloxone-sensitivity and non-classical opioid rank order of effect were all observed. These data support the non-classical opioid nature of direct opioid modulation of splenocyte proliferation.

BrainPhys neuronal medium optimized for imaging and optogenetics in vitro

Publisher: Springer Science and Business Media LLC

Date: 03-11-2020

DOI: 10.1038/S41467-020-19275-X

Abstract: The capabilities of imaging technologies, fluorescent sensors, and optogenetics tools for cell biology are advancing. In parallel, cellular reprogramming and organoid engineering are expanding the use of human neuronal models in vitro. This creates an increasing need for tissue culture conditions better adapted to live-cell imaging. Here, we identify multiple caveats of traditional media when used for live imaging and functional assays on neuronal cultures (i.e., suboptimal fluorescence signals, phototoxicity, and unphysiological neuronal activity). To overcome these issues, we develop a neuromedium called BrainPhys™ Imaging (BPI) in which we optimize the concentrations of fluorescent and phototoxic compounds. BPI is based on the formulation of the original BrainPhys medium. We benchmark available neuronal media and show that BPI enhances fluorescence signals, reduces phototoxicity and optimally supports the electrical and synaptic activity of neurons in culture. We also show the superior capacity of BPI for optogenetics and calcium imaging of human neurons. Altogether, our study shows that BPI improves the quality of a wide range of fluorescence imaging applications with live neurons in vitro while supporting optimal neuronal viability and function.

Sensitive cytokine assay based on optical fiber allowing localized and spatially resolved detection of interleukin-6

Publisher: American Chemical Society (ACS)

Date: 29-12-2017

DOI: 10.1021/ACSSENSORS.6B00619

Abstract: We demonstrated a cytokine detection device based on gold nanoparticle modified silica optical fiber for the monitoring of locally variable cytokine interleukin-6 (IL-6) concentrations using a sandwich immunoassay scheme. The fiber is designed to be introduced into an intrathecal catheter with micrometer-sized holes drilled along its length to enable fluid exchange between the outside and inside of the catheter. An exposed optical fiber (diameter 125 μm) modified with a layer of gold nanoparticles was functionalized with the IL-6 capture antibody to form the sensing interface. The immunocapture device was incubated with a cytokine solution to capture the analyte. The device was then exposed to the IL-6 detection antibody which was loaded on the fluorescently labeled magnetic nanoparticles, making it possible to quantify the cytokine concentration based on the intensity of fluorescence. A reliable method for quantifying the fluorescent signal on a 3D structure was developed. This device was applied to the detection of cytokine IL-6 with the low limit of detection of 1 pg mL

Shapeshifting photoswitchable azobenzene compounds and their biological applications

Publisher: SPIE

Date: 24-11-2016

DOI: 10.1117/12.2242356

Quantification of the O- and N-demethylated metabolites of hydrocodone and oxycodone in human liver microsomes using liquid chromatography with ultraviolet absorbance detection1

Publisher: Elsevier BV

Date: 25-02-2003

DOI: 10.1016/S1570-0232(02)00856-5

Toll‐like receptor 4 in CNS pathologies

Publisher: Wiley

Date: 08-06-2010

DOI: 10.1111/J.1471-4159.2010.06736.X

Differential effect of morphine on gastrointestinal transit, colonic contractions and nerve-evoked relaxations in Toll-Like Receptor deficient mice

Publisher: Springer Science and Business Media LLC

Date: 12-04-2018

DOI: 10.1038/S41598-018-23717-4

Abstract: Toll-like receptors (TLRs) are expressed in enteric neurons, glia, gastrointestinal (GI) smooth muscle and mucosa, yet their functional roles in the GI tract are not fully understood. TLRs have been linked to many of the undesirable central effects of chronic opioid administration including hyperalgesia and dependence via activation of central microglia. Opioid-induced bowel dysfunction (OIBD) remains a primary reason for the reduction or withdrawal of opioid analgesics. Morphine-induced inhibition of colonic motility was assessed in vivo by GI transit studies and in vitro using isolated colons from wildtype (WT) and TLR deficient mice. Morphine slowed movement of ingested content in WT but this retardation effect was attenuated in TLR4 −/− and TLR2/4 −/− . In isolated colons, morphine reduced litude and frequency colonic migrating motor contractions in both WT and TLR2/4 −/− . Electrical field stimulation elicited distal colon relaxation that was potentiated by morphine in WT but not in TLR2/4 −/− . Inhibitory junction potentials were of similar litude and kinetics in WT and TLR2/4 −/− distal colon and not altered by morphine. Enteric nerve density and proportion of nitrergic nerves were similar in WT and TLR2/4 −/− distal colon. These data suggest an involvement of TLRs in opioid pharmacodynamics and thus a potential interventional target for OIBD.

Are the effects of alcohol on the CNS influenced by Toll-like receptor signaling?

Publisher: Informa UK Limited

Date: 03-2012

DOI: 10.1586/ECI.11.99

Evidence that opioids may have toll-like receptor 4 and MD-2 effects

Publisher: Elsevier BV

Date: 2010

DOI: 10.1016/J.BBI.2009.08.004

Very early assessment of risk for in-hospital death among 11,483 patients with acute myocardial infarction

Publisher: Elsevier BV

Date: 12-1999

DOI: 10.1016/S0002-8703(99)70070-0

Abstract: The efficacy of reperfusion therapy after acute myocardial infarction is time dependent. The risk profile of every patient should be available as soon as possible. Our aim was to determine whether collection of simple clinical markers at hospital admission might allow reliable risk stratification for in-hospital mortality. The subjects were 11,483 patients with acute myocardial infarction from the GISSI-2 cohort. The GISSI-1 and GISSI-3 populations were selected to validate the classification. To stratify patients, the tree-growing method called recursive partitioning and amalgamation (RECPAM) was used. This method is used to identify homogeneous and distinct subgroups with respect to outcome. The RECPAM algorithm provided 6 classes. RECPAM class I included Killip class 3 to class 4 patients (516 deaths/1000). RECPAM class II included Killip 2 patients older than 66 years and with anterior infarction or sites of infarction that could not be evaluated (314 deaths/1000). Killip 1 patients older than 75 years and with anterior or multiple sites or sites that could not be evaluated were included in RECPAM class III with Killip class 2 patients younger than 66 years and with systolic blood pressure less than 120 mm Hg or older than 66 years and with any other infarction site (207 deaths/1000). The other classes showed lower mortality rates (91, 32, and 12 deaths/1000 for RECPAM classes IV, V, and VI). In the GISSI 1 and GISSI 3 s les the 6 classes ranked in the same order in terms of mortality rate. With respect to low-risk strata, patients belonging to RECPAM class VI without serious clinical events in the first 4 days had a very low incidence of in-hospital death (0.9%) or morbidity. Cumulative 6-month mortality for the 6 RECPAM classes was 59.6%, 41.2%, 26.4%, 12.9%, 4. 8%, and 2.2%. Four simple clinical markers readily available at admission of patients with myocardial infarction allow a quick, reliable, and inexpensive prediction of risk for in-hospital and 6-month mortality. The RECPAM classification also helped identify a large subgroup of patients fit for early hospital discharge.

Pharmacological characterization of the opioid inactive isomers (+)‐naltrexone and (+)‐naloxone as antagonists of toll‐like receptor 4

Publisher: Wiley

Date: 04-02-2016

DOI: 10.1111/BPH.13394

Want more pain? Just add a dash of endotoxin to enhance your clinical pain model

Publisher: Elsevier BV

Date: 10-2014

DOI: 10.1016/J.BBI.2014.06.008

Toll-like receptors change morphine-induced antinociception, tolerance and dependence: Studies using male and female TLR and signalling gene KO mice

Publisher: Elsevier BV

Date: 05-2022

DOI: 10.1016/J.BBI.2022.02.001

Abstract: Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling potentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2

The “Toll” of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia

Publisher: Elsevier BV

Date: 11-2009

DOI: 10.1016/J.TIPS.2009.08.002

Mouse models of mastitis – how physiological are they?

Publisher: Springer Science and Business Media LLC

Date: 26-03-2015

DOI: 10.1186/S13006-015-0038-5

Long-term intrathecal administration of morphine vs. baclofen

Publisher: Oxford University Press (OUP)

Date: 09-09-2022

DOI: 10.1093/GLYCOB/CWAB098

Abstract: Opioid use for treatment of persistent pain has increased dramatically over the past two decades, but it has not resulted in improved pain management outcomes. To understand the molecular mechanisms of opioids, molecular signatures that arise from opioid exposure are often sought after, using various analytical methods. In this study, we performed proteomics, and multiglycomics via sequential analysis of polysialic acids, glycosaminoglycans, N-glycans and O-glycans, using the same cerebral spinal fluid (CSF) s le from patients that had long-term (& years), intrathecal morphine or baclofen administered via an indwelling pump. Proteomics and N-glycomics signatures between the two treatment groups were highly conserved, while significant differences were observed in polysialic acid, heparan sulfate glycosaminoglycan and O-glycan profiles between the two treatment groups. This represents the first study to investigate the potential relationships between erse CSF conjugated glycans and long-term intrathecal drug exposure. The unique changes, observed by a sequential analytical workflow, reflect previously undescribed molecular effects of opioid administration and pain management.

Measurements of vitamin B12 in human blood serum using resonance Raman spectroscopy

Publisher: SPIE

Date: 09-12-2016

DOI: 10.1117/12.2244620

Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial

Publisher: Wiley

Date: 03-2012

DOI: 10.1093/EURJHF/HFS007

Abstract: Abnormal liver function tests (LFTs) are common in ambulatory heart failure (HF). The aim of this study was to characterize abnormal LFTs during index hospitalization. A post-hoc analysis was carried out of the placebo group of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial, which enrolled patients hospitalized for HF with an ejection fraction (EF) ≤40% and no history of primary significant liver disease or acute hepatic failure. LFTs (abbreviation, cut-offs for abnormal values) including serum albumin (ALB, 34 IU/L), alanine transaminase (ALT, >34 IU/L), alkaline phosphatase (AP, >123 IU/L),γ-glutamyl transferase (GGT, >50 IU/L), and total bilirubin (T Bili, >1.2 mg/dL) were measured at baseline, discharge/day 7, and post-discharge. Co-primary endpoints were all-cause mortality (ACM) and cardiovascular mortality or first HF hospitalization (CVM + HFH). Study participants had a mean age of 65.6 ±12.0 years, were mostly male, reported high prevalences of medical co-morbidities, and were well treated with evidence-based therapies. Baseline LFT abnormalities were common (ALB 17%, AST 21%, ALT 21%, AP 23%, GGT 62%, and T Bili 26%). Abnormal T Bili was the only marker to decrease substantially from baseline (26%) to discharge/day 7 (19%). All LFTs, except AP, improved post-discharge. Lower baseline ALB and elevated T Bili were associated with higher rates of ACM, and in-hospital decreases in ALB and increases in T Bili were associated with higher rates of both ACM and CVM + HFH. LFT abnormalities are common during hospitalization for HF in patients with reduced EF and were persistent at discharge. Baseline and in-hospital changes in ALB and T Bili provide additional prognostic value.

Hollow core optical fibres made by glass billet extrusion as sensors for Raman spectroscopy

Publisher: SPIE

Date: 09-12-2016

DOI: 10.1117/12.2244625

In vitro opioid induced proliferation of peripheral blood immune cells correlates with in vivo cold pressor pain tolerance in humans: a biological marker of pain tolerance

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-2004

DOI: 10.1016/J.PAIN.2004.05.017

The importance of knowing you are sick: Nanoscale biophotonics for the 'other' brain

Publisher: Elsevier BV

Date: 02-2018

DOI: 10.1016/J.MEE.2017.12.007

Motility/Neurogastroenterology

Publisher: Wiley

Date: 10-2014

DOI: 10.1111/JGH.12736_8

Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences

Publisher: Elsevier BV

Date: 05-2010

DOI: 10.1016/J.NEUROSCIENCE.2010.02.011

Erratum

Publisher: Informa UK Limited

Date: 03-2013

DOI: 10.1586/ERN.13.21

Known and missing left ventricular ejection fraction and survival in patients with heart failure: a MAGGIC meta‐analysis report

Publisher: Wiley

Date: 11-2013

DOI: 10.1093/EURJHF/HFT101

Abstract: Treatment of patients with heart failure (HF) relies on measurement of LVEF. However, the extent to which EF is recorded varies markedly. We sought to characterize the patient group that is missing a measure of EF, and to explore the association between missing EF and outcome. In idual data on 30 445 patients from 28 observational studies in the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) project were used to compare the prevalence of co-morbidities and outcome across three groups of HF patients: those with missing EF (HF-mEF), reduced EF (HF-REF), and preserved EF (HF-PEF). A total of 29% had HF-mEF, 52% HF-REF, and 19% HF-PEF. Compared with patients in whom EF was known, patients with HF-mEF were older, had a greater prevalence of COPD and previous stroke, and were smokers. Patients with HF-mEF were less likely to receive evidence-based treatment than those with HF-REF. Adjusted mortality in HF-mEF was similar to that in HF-REF and greater than that in HF-PEF at 3 years [HF-REF, hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.95-1.12) HF-PEF, HR 0.78, 95% CI 0.71-0.86]. Missing EF is common. The short- and long-term outcome of patients with HF-mEF is poor and they exhibit different co-morbidity profiles and treatment patterns compared with patients with known EF. HF patients with missing EF represent a high risk group.

(S)-(+)-methadone is more immunosuppressive than the potent analgesic (R)-(−)-methadone

Publisher: Elsevier BV

Date: 11-2004

DOI: 10.1016/J.INTIMP.2004.07.011

Review: What innovations in pain measurement and control might be possible if we could quantify the neuroimmune synapse?

Publisher: Elsevier BV

Date: 2019

DOI: 10.1017/S1751731119001885

Toll-Like Receptor-4 Antagonist (+)-Naloxone Confers Sexually Dimorphic Protection From Inflammation-Induced Fetal Programming in Mice

Publisher: The Endocrine Society

Date: 27-08-2019

DOI: 10.1210/EN.2019-00493

Abstract: Inflammation elicited by infection or noninfectious insults during gestation induces proinflammatory cytokines that can shift the trajectory of development to alter offspring phenotype, promote adiposity, and increase susceptibility to metabolic disease in later life. In this study, we use mice to investigate the utility of a small molecule Toll-like receptor (TLR)4 antagonist (+)-naloxone, the nonopioid isomer of the opioid receptor antagonist (−)-naloxone, for mitigating altered fetal metabolic programming induced by a modest systemic inflammatory challenge in late gestation. In adult progeny exposed to lipopolysaccharide (LPS) challenge in utero, male but not female offspring exhibited elevated adipose tissue, reduced muscle mass, and elevated plasma leptin at 20 weeks of age. Effects were largely reversed by coadministration of (+)-naloxone following LPS. When given alone without LPS, (+)-naloxone elicited accelerated postweaning growth and elevated muscle and fat mass in adult male but not female offspring. LPS induced expression of inflammatory cytokines Il1a, Il1b, Il6, Tnf, and Il10 in fetal brain, placental, and uterine tissues, and (+)-naloxone suppressed LPS-induced cytokine expression. Fetal sex-specific regulation of cytokine expression was evident, with higher Il1a, Il1b, Il6, and Il10 induced by LPS in tissues associated with male fetuses, and greater suppression by (+)-naloxone of Il6 in females. These data demonstrate that modulating TLR4 signaling with (+)-naloxone provides protection from inflammatory ersion of fetal developmental programming in utero, associated with attenuation of gestational tissue cytokine expression in a fetal sex-specific manner. The results suggest that pharmacologic interventions targeting TLR4 warrant evaluation for attenuating developmental programming effects of fetal exposure to maternal inflammatory mediators.

The Wiley‐Blackwell Handbook of Psychoneuroimmunology

Publisher: Wiley

Date: 11-2013

DOI: 10.1002/9781118314814

Appropriateness of Prescriptions of Recommended Treatments in Organisation for Economic Co-operation and Development Health Systems: Findings Based on the Long-Term Registry of the European Society of

Publisher: Elsevier BV

Date: 12-2015

DOI: 10.1016/J.JVAL.2015.08.005

Abstract: This observational study aimed to identify clinical variables and health system characteristics associated with incomplete guideline application in drug treatment of patients with chronic heart failure (HF) across 15 countries. Three data sets were used: European Society of Cardiology Heart Failure Registry, Organisation for Economic Co-operation and Development's Health System Characteristics Survey, and Organisation for Economic Co-operation and Development Health Statistics 2013. Patient and country variables were examined by multilevel, multiple logistic regression. The study population consisted of ambulatory patients with chronic HF and reduced ejection fraction. Inappropriateness of prescription of pharmacological treatments was defined as patients not prescribed at least one of the two recommended treatments (angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers and beta-blockers) or treated with both medications but at suboptimal dosage and in absence of documented contraindication/intolerance. Of 4605 patients, 1097 (23.8%) received inappropriate drug prescriptions with a large variation within and across countries, with 18.5% of the total variability accounted for by between-country health structure characteristics. Patient-level characteristics such as having mitral regurgitation (odds ratio 1.4 95% confidence interval 1.1-1.7) was significantly associated with inappropriate prescription of recommended drugs, whereas chronic obstructive pulmonary disease (odds ratio 0.7 95% confidence interval 0.5-0.9) was associated with more appropriate prescriptions. Among the country-level variables, incentives or obligation to comply with guidelines increased the probability of prescription appropriateness. Combining clinical variables with health system characteristics is a promising exercise to explain the appropriateness of recommended drug prescriptions. Such an understanding can help decision makers to design more effective policies to improve adherence to guidelines, improve health care outcomes, and potentially reduce costs.

Glia: novel counter-regulators of opioid analgesia

Publisher: Elsevier BV

Date: 12-2005

DOI: 10.1016/J.TINS.2005.10.001

Abstract: Development of analgesic tolerance and withdrawal-induced pain enhancement present serious difficulties for the use of opioids for pain control. Although neuronal mechanisms to account for these phenomena have been sought for many decades, their bases remain unresolved. Within the past four years, a novel non-neuronal candidate has been uncovered that opposes acute opioid analgesia and contributes to development of opioid tolerance and tolerance-associated pain enhancement. This novel candidate is spinal cord glia. Glia are important contributors to the creation of enhanced pain states via the release of neuroexcitatory substances. New data suggest that glia also release neuroexcitatory substances in response to morphine, thereby opposing its effects. Controlling glial activation could therefore increase the clinical utility of analgesic drugs.

Non‐stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll‐like receptor 4 (TLR4)

Publisher: Wiley

Date: 07-2008

DOI: 10.1111/J.1460-9568.2008.06321.X

The cortical innate immune response increases local neuronal excitability leading to seizures

Publisher: Oxford University Press (OUP)

Date: 30-06-2009

DOI: 10.1093/BRAIN/AWP177

Three new species of Stiphrornis (Aves: Muscicapidae) from the Afro-tropics, with a molecular phylogenetic assessment of the genus

Publisher: Informa UK Limited

Date: 28-09-2016

DOI: 10.1080/14772000.2016.1226978

Adoptive transfer of peripheral immune cells potentiates allodynia in a graded chronic constriction injury model of neuropathic pain

Publisher: Elsevier BV

Date: 03-2011

DOI: 10.1016/J.BBI.2010.11.018

Abstract: Recent evidence demonstrates that peripheral immune cells contribute to the nociceptive hypersensitivity associated with neuropathic pain by infiltrating the central nervous system (CNS). We have recently developed a rat model of graded chronic constriction injury (CCI) by varying the exposure of the sciatic nerve and control non-nerve tissue to surgical placement of chromic gut. We demonstrate that splenocytes can contribute significantly to CCI-induced allodynia, as adoptive transfer of these cells from high pain donors to low pain recipients potentiates allodynia (P<0.001). The phenomenon was replicated with peripheral blood mononuclear cells (P<0.001). Adoptive transfer of allodynia was not achieved in sham recipients, indicating that peripheral immune cells are only capable of potentiating existing allodynia, rather than establishing allodynia. As adoptively transferred cells were found by flow cytometry to migrate to the spleen (P<0.05) and potentiation of allodynia was prevented in splenectomised low pain recipients, adoptive transfer of high pain splenocytes may induce the migration of host-derived immune cells from the spleen to the CNS as observed by flow cytometry (P<0.05). Importantly, intrathecal transfer of CD45(+) cells prepared from spinal cords of high pain donors into low pain recipients led to potentiated allodynia (P<0.001), confirming that infiltrating immune cells are not passive bystanders, but actively contribute to nociceptive hypersensitivity in the lumbar spinal cord.

Role of microglia and toll-like receptor 4 in the pathophysiology of delirium

Publisher: Elsevier BV

Date: 12-2012

DOI: 10.1016/J.MEHY.2012.08.013

Abstract: Delirium is a serious medical condition that commonly afflicts elderly inpatients. This is especially common in the post-operative setting where it increases mortality, length of hospital stay and health care costs. The exact mechanisms involved in its pathogenesis remain uncertain and there is currently no effective pharmacological therapy for treatment or prevention of delirium. We hypothesize that microglia-mediated neuroinflammation via toll-like receptor 4 signalling is a significant contributor to post-operative delirium. Based on our proposed mechanism, three novel pharmacological therapies have been suggested to be effective to prevent or treat delirium. Curcumin, ibudilast and minocycline have been shown to interfere with various steps in the proinflammatory microglial activation intracellular signalling pathway, disrupting the subsequent neuroinflammatory cascade. We hypothesize that these drugs could be a novel pharmacotherapy that could significantly improve the outcome of post-operative delirious patients.

Study protocol: an observational study of distress, immune function and persistent pain in HIV

Publisher: BMJ

Date: 06-2022

DOI: 10.1136/BMJOPEN-2021-059723

Abstract: Many people with HIV report both distress and pain. The relationship between distress and pain is bidirectional, but the mechanisms by which distress exacerbates pain are unclear. The inflammatory response to challenge (inflammatory reactivity, IR) may be a partial mediator, given that neuroimmune interactions provide a substrate for IR to also influence neurological reactivity and, thus, pain-related neural signalling. This prospective, observational, case–control study will characterise the relationships between distress, IR, pain-related signalling as captured by induced secondary hyperalgesia (SH), and pain, in people with HIV who report persistent pain (PP) (cases) or no pain (controls). One hundred people with suppressed HIV, reporting either PP or no pain, will be assessed two or four times over 6 months. The primary outcomes are distress (Hopkins 25-item symptom checklist), IR (multiplex assay after LPS challenge), and PP (Brief Pain Inventory), assessed at the baseline timepoint, although each will also be assessed at follow-up time points. Induced SH will be assessed in a subs le of 60 participants (baseline timepoint only). To test the hypothesis that IR partly mediates the relationship between distress and pain, mediation analysis will use the baseline data from the PP group to estimate direct and indirect contributions of distress and IR to pain. To test the hypothesis that IR is positively associated with SH, data from the subs le will be analysed with generalised mixed effects models to estimate the association between IR and group membership, with SH as the dependent variable. Information obtained from this study will be published in peer-reviewed journals and presented at scientific meetings. The study has been approved by the Human Research Ethics Committee of the University of Cape Town (approval number: 764/2019) and the City of Cape Town (ref: 24699). NCT04757987 .

Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity

Publisher: Elsevier BV

Date: 06-2010

DOI: 10.1016/J.NEUROSCIENCE.2010.03.067

Autofluorescent imprint of chronic constriction nerve injury identified by deep learning

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.NBD.2021.105528

Abstract: Our understanding of chronic pain and the underlying molecular mechanisms remains limited due to a lack of tools to identify the complex phenomena responsible for exaggerated pain behaviours. Furthermore, currently there is no objective measure of pain with current assessment relying on patient self-scoring. Here, we applied a fully biologically unsupervised technique of hyperspectral autofluorescence imaging to identify a complex signature associated with chronic constriction nerve injury known to cause allodynia. The analysis was carried out using deep learning/artificial intelligence methods. The central element was a deep learning autoencoder we developed to condense the hyperspectral channel images into a four- colour image, such that spinal cord tissue based on nerve injury status could be differentiated from control tissue. This study provides the first validation of hyperspectral imaging as a tool to differentiate tissues from nerve injured vs non-injured mice. The auto-fluorescent signals associated with nerve injury were not diffuse throughout the tissue but formed specific microscopic size regions. Furthermore, we identified a unique fluorescent signal that could differentiate spinal cord tissue isolated from nerve injured male and female animals. The identification of a specific global autofluorescence fingerprint associated with nerve injury and resultant neuropathic pain opens up the exciting opportunity to develop a diagnostic tool for identifying novel contributors to pain in in iduals.

Postbreeding Habitat Use by Golden-Cheeked Warblers (Setophaga chrysoparia)

Publisher: Western North American Naturalist

Date: 09-10-2019

DOI: 10.3398/064.079.0305

Graphene quantum dot based switch-on nanosensors for intracellular cytokine monitoring

Publisher: Royal Society of Chemistry (RSC)

Date: 2017

DOI: 10.1039/C6NR09381G

Abstract: The detection of cytokines in body fluids, cells, tissues and organisms continues to attract considerable attention due to the importance of these key cell signalling molecules in biology and medicine. We report a graphene quantum dot (GQD) based aptasensor able to specifically detect ultra-small amounts of cytokine molecules intracellularly. Graphene quantum dots modified with cytokine aptamers (Ap-GQDs) and epitope modified GQDs (Ep-GQDs) were prepared both are normally fluorescent at sufficient dilution. However, the fluorescence of the conjugates of Ap-GQDs and Ep-GQDs is quenched due to aggregation between Ap-GQDs and Ep-GQDs. After incubation of the cytokine-secreting cells with the conjugates of Ap-GQDs and Ep-GQDs, the cytokines secreted in cells compete for binding with the epitope which is then displaced. The ensuing binding of cytokines with the aptamers results in the disaggregation of Ap-GQDs and Ep-GQDs, and the recovery of fluorescence. The conjugates of Ap-GQDs and Ep-GQDs were used as nanosensors for monitoring intracellular cytokine IFN-γ secretion with very high sensitivity (2 pg mL

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials

Publisher: Elsevier BV

Date: 11-2010

DOI: 10.1016/S0140-6736(10)61350-5

Evaluation of miRNA as Biomarkers of Emotional Valence in Pigs

Publisher: MDPI AG

Date: 09-07-2021

DOI: 10.3390/ANI11072054

Abstract: The ability to assess the welfare of animals is dependent on our ability to accurately determine their emotional (affective) state, with particular emphasis being placed on the identification of positive emotions. The challenge remains that current physiological and behavioral indices are either unable to distinguish between positive and negative emotional states, or they are simply not suitable for a production environment. Therefore, the development of novel measures of animal emotion is a necessity. Here we investigated the efficacy of microRNA (miRNA) in the brain and blood as biomarkers of emotional state in the pig. Female Large White × Landrace pigs (n = 24) were selected at weaning and trained to perform a judgment bias test (JBT), before being exposed for 5 weeks to either enriched (n = 12) or barren housing (n = 12) conditions. Pigs were tested on the JBT once prior to treatment, and immediately following treatment. MiRNA and neurotransmitters were analyzed in blood and brain tissue after euthanasia. Treatment had no effect on the outcomes of the JBT. There was also no effect of treatment on miRNA expression in blood or the brain (FDR p 0.05). However, pigs exposed to enriched housing had elevated dopamine within the striatum compared to pigs in barren housing (p = 0.02). The results imply that either (a) miRNAs are not likely to be valid biomarkers of a positive affective state, at least under the type of conditions employed in this study, or (b) that the study design used to modify affective state was not able to create differential affective states, and therefore establish the validity of miRNA as biomarkers.

Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4

Publisher: Bentham Science Publishers Ltd.

Date: 24-06-2015

DOI: 10.2174/1871527314666150529132503

Abstract: There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, meth hetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drugprimed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse.

ABSTRACTS FROM THE 10^THINTERNATIONAL ISSX MEETING

Publisher: Informa UK Limited

Date: 2014

DOI: 10.3109/03602532.2013.868114

The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis

Publisher: Oxford University Press (OUP)

Date: 06-08-2011

DOI: 10.1093/EURHEARTJ/EHR254

Abstract: A substantial proportion of patients with heart failure have preserved left ventricular ejection fraction (HF-PEF). Previous studies have reported mixed results whether survival is similar to those patients with heart failure and reduced EF (HF-REF). We compared survival in patients with HF-PEF with that in patients with HF-REF in a meta-analysis using in idual patient data. Preserved EF was defined as an EF ≥ 50%. The 31 studies included 41 972 patients: 10 347 with HF-PEF and 31 625 with HF-REF. Compared with patients with HF-REF, those with HF-PEF were older (mean age 71 vs. 66 years), were more often women (50 vs. 28%), and have a history of hypertension (51 vs. 41%). Ischaemic aetiology was less common (43 vs. 59%) in patients with HF-PEF. There were 121 [95% confidence interval (CI): 117, 126] deaths per 1000 patient-years in those with HF-PEF and 141 (95% CI: 138, 144) deaths per 1000 patient-years in those with HF-REF. Patients with HF-PEF had lower mortality than those with HF-REF (adjusted for age, gender, aetiology, and history of hypertension, diabetes, and atrial fibrillation) hazard ratio 0.68 (95% CI: 0.64, 0.71). The risk of death did not increase notably until EF fell below 40%. Patients with HF-PEF have a lower risk of death than patients with HF-REF, and this difference is seen regardless of age, gender, and aetiology of HF. However, absolute mortality is still high in patients with HF-PEF highlighting the need for a treatment to improve prognosis.

Naturally-diverse airborne environmental microbial exposures modulate the gut microbiome and may provide anxiolytic benefits in mice

Publisher: Elsevier BV

Date: 2020

DOI: 10.1016/J.SCITOTENV.2019.134684

Abstract: Growing epidemiological evidence links natural green space exposure with a range of health benefits, including for mental health. Conversely, greater urbanisation associates with increased risk of mental health disorders. Microbiomes are proposed as an important but understudied link that may help explain many green space-human health associations. However, there remains a lack of controlled experimental evidence testing possible beneficial effects from passive exposure to natural bio ersity via airborne microbiota. Previous mouse model studies have used unrealistic environmental microbial exposures-including excessive soil and organic matter contact, feed supplements and injections-to demonstrate host microbiota, immune biomarker, and behavioural changes. Here, in a randomised controlled experiment, we demonstrate that realistic exposures to trace-level dust from a high bio ersity soil can change mouse gut microbiota, in comparison to dust from low bio ersity soil or no soil (control) (n = 54 total mice, comprising 3 treatments × 18 mice, with 9 females + 9 males per group). Furthermore, we found a nominal soil-derived anaerobic spore-forming butyrate-producer, Kineothrix alysoides, was supplemented to a greater extent in the gut microbiomes of high bio ersity treatment mice. Also, increasing relative abundance of this rare organism correlated with reduced anxiety-like behaviour in the most anxious mice. Our results point to an intriguing new hypothesis: that bio erse soils may represent an important supplementary source of butyrate-producing bacteria capable of resupplying the mammalian gut microbiome, with potential for gut health and mental health benefits. Our findings have potential to inform cost-effective population health interventions through microbiome-conscious green space design and, ultimately, the mainstreaming of bio ersity into health care.

Drug Addiction

Publisher: Springer New York

Date: 2014

DOI: 10.1007/978-1-4939-1429-6_12

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

Publisher: Massachusetts Medical Society

Date: 28-09-2017

DOI: 10.1056/NEJMOA1706444

Changes in body weight and pulse: outcome events in overweight and obese subjects with cardiovascular disease in the SCOUT trial

Publisher: Springer Science and Business Media LLC

Date: 18-12-2014

DOI: 10.1038/IJO.2014.211

Abstract: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment with diet and exercise. We examined the relationship between early changes (both increases and decreases) in pulse rate, and the impact of these changes on subsequent cardiovascular outcome events in both the placebo and sibutramine groups. 9804 males and females, aged ⩾55 years, with a body mass index of 27-45 kg m(-)(2) were included in this current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one cardiovascular risk factor, to assess cardiovascular outcomes. The primary outcome event (POE) was a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event analyses of the POE were performed using Cox regression models. During the initial 6-week sibutramine treatment period, the induced pulse rate increase was related to weight change (1.9±7.7 beats per minute (bpm) with weight increase 1.4±7.3 bpm, 0-5 kg weight loss 0.6±7.4 bpm, ⩾5 kg weight loss). Throughout the subsequent treatment period, those continuing on sibutramine showed a consistently higher mean pulse rate than the placebo group. There was no difference in POE rates with either an increase or decrease in pulse rate over the lead-in period, or during lead-in baseline to 12 months post randomization. There was also no relationship between pulse rate at lead-in baseline and subsequent cardiovascular events in subjects with or without a cardiac arrhythmia. Baseline pulse rate and changes in pulse rate may not be an important modifier nor a clinically useful predictor of outcome in an in idual elderly cardiovascular obese subject exposed to weight management.

Morphine activates neuroinflammation in a manner parallel to endotoxin

Publisher: Proceedings of the National Academy of Sciences

Date: 02-04-2012

DOI: 10.1073/PNAS.1200130109

Abstract: Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.

Increased responsiveness of peripheral blood mononuclear cells to in vitro TLR 2, 4 and 7 ligand stimulation in chronic pain patients.

Publisher: Public Library of Science (PLoS)

Date: 28-08-2012

DOI: 10.1371/JOURNAL.PONE.0044232

Spiropyran‐Based Nanocarrier: A New Zn2+‐Responsive Delivery System with Real‐Time Intracellular Sensing Capabilities

Publisher: Wiley

Date: 13-12-2019

DOI: 10.1002/CHEM.201804816

Abstract: A new spiropyran-based stimuli-responsive delivery system is fabricated. It encapsulates and then releases an extraneous compound in response to elevated levels of Zn

Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation

Publisher: Springer Science and Business Media LLC

Date: 11-11-2014

DOI: 10.1038/TP.2014.121

Attenuating Glial Activation with Minocycline Reduces the Hyperthermic Response to 3, 4-Methylenedioxymethamphetamine (MDMA) In the Rat

Publisher: Bentham Science Publishers Ltd.

Date: 29-03-2011

DOI: 10.2174/1874941001104010004

Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats

Publisher: Elsevier BV

Date: 12-2009

DOI: 10.1016/J.NEUROSCIENCE.2009.09.046

Implications of central immune signaling caused by drugs of abuse: Mechanisms, mediators and new therapeutic approaches for prediction and treatment of drug dependence

Publisher: Elsevier BV

Date: 05-2012

DOI: 10.1016/J.PHARMTHERA.2012.01.008

Abstract: In the past two decades a trickle of manuscripts examining the non-neuronal central nervous system immune consequences of the drugs of abuse has now swollen to a significant body of work. Initially, these studies reported associative evidence of central nervous system proinflammation resulting from exposure to the drugs of abuse demonstrating key implications for neurotoxicity and disease progression associated with, for ex le, HIV infection. However, more recently this drug-induced activation of central immune signaling is now understood to contribute substantially to the pharmacodynamic actions of the drugs of abuse, by enhancing the engagement of classical mesolimbic dopamine reward pathways and withdrawal centers. This review will highlight the key in vivo animal, human, biological and molecular evidence of these central immune signaling actions of opioids, alcohol, cocaine, meth hetamine, and 3,4-methylenedioxymeth hetamine (MDMA). Excitingly, this new appreciation of central immune signaling activity of drugs of abuse provides novel therapeutic interventions and opportunities to identify 'at risk' in iduals through the use of immunogenetics. Discussion will also cover the evidence of modulation of this signaling by existing clinical and pre-clinical drug candidates, and novel pharmacological targets. Finally, following examination of the breadth of central immune signaling actions of the drugs of abuse highlighted here, the current known common immune signaling components will be outlined and their impact on established addiction neurocircuitry discussed, thereby synthesizing a common neuroimmune hypothesis of addiction.

Harnessing pain heterogeneity and RNA transcriptome to identify blood‐based pain biomarkers: a novel correlational study design and bioinformatics approach in a graded chronic constriction injury mode

Publisher: Wiley

Date: 09-07-2012

DOI: 10.1111/J.1471-4159.2012.07833.X

Application of a novel in silico high-throughput screen to identify selective inhibitors for protein–protein interactions

Publisher: Elsevier BV

Date: 09-2010

DOI: 10.1016/J.BMCL.2010.07.103

Effect of exercise on chronic neck pain and central sensitization: A protocol for a randomized crossover trial

Publisher: Wiley

Date: 29-03-2023

DOI: 10.1113/EP091065

Abstract: Exercise‐induced hypoalgesia (EIH) has been found to vary widely within in iduals with chronic neck pain (NP). Research has suggested that the presence of central sensitization within a subgroup of in iduals with chronic NP might be a mediating factor to explain the relationship between exercise and improvements in patient‐reported outcomes. Furthermore, recent work has found that lactate might play a role in the development and maintenance of chronic pain. The immediate effect of a single bout of physical exercise on central sensitization in in iduals with chronic NP and the relationship between lactate concentration, central sensitization and pain sensitivity are to be investigated. Eighty adult participants with chronic NP will be recruited for this randomized crossover trial. Outcome measures, including temporal summation, conditioned pain modulation, EIH and lactate concentration, will be assessed before and after low‐ and high‐intensity bicycling exercise. The outcomes of this study will provide new insights into the mechanistic effect of exercise on central sensitization in in iduals with chronic NP and have the potential to add important information to the current exercise prescription guidelines for in iduals with chronic NP. This study has been approved by the Human Research Ethics Committee, The University of Adelaide (H‐2022‐082) and registered in the Australian New Zealand Clinical Trials Registry (ACTRN12622000642785p).

Influence of socioeconomic factors on pregnancy outcome in women with structural heart disease

Publisher: BMJ

Date: 11-2017

DOI: 10.1136/HEARTJNL-2017-311910

Abstract: Cardiac disease is the leading cause of indirect maternal mortality. The aim of this study was to analyse to what extent socioeconomic factors influence the outcome of pregnancy in women with heart disease. The Registry of Pregnancy and Cardiac disease is a global prospective registry. For this analysis, countries that enrolled ≥10 patients were included. A combined cardiac endpoint included maternal cardiac death, arrhythmia requiring treatment, heart failure, thromboembolic event, aortic dissection, endocarditis, acute coronary syndrome, hospitalisation for cardiac reason or intervention. Associations between patient characteristics, country characteristics (income inequality expressed as Gini coefficient, health expenditure, schooling, gross domestic product, birth rate and hospital beds) and cardiac endpoints were checked in a three-level model (patient–centre–country). A total of 30 countries enrolled 2924 patients from 89 centres. At least one endpoint occurred in 645 women (22.1%). Maternal age, New York Heart Association classification and modified WHO risk classification were associated with the combined endpoint and explained 37% of variance in outcome. Gini coefficient and country-specific birth rate explained an additional 4%. There were large differences between the in idual countries, but the need for multilevel modelling to account for these differences disappeared after adjustment for patient characteristics, Gini and country-specific birth rate. While there are definite interregional differences in pregnancy outcome in women with cardiac disease, these differences seem to be mainly driven by in idual patient characteristics. Adjustment for country characteristics refined the results to a limited extent, but maternal condition seems to be the main determinant of outcome.

Androgens, Endometriosis and Pain

Publisher: Frontiers Media SA

Date: 03-12-2021

DOI: 10.3389/FRPH.2021.792920

Abstract: The intriguing relationship between androgens, endometriosis and chronic pain continues to unfold. Determining this relationship is of crucial importance to gynecologists managing people with these conditions, as common treatments dramatically alter her hormonal profiles, with both intended and unintended consequences. Although they may be present in the same in idual, there is a recognized disconnect between pain or pain-related symptoms, and the presence or extent of endometriosis lesions. Reduced androgen levels provide a potential mechanism to link the development of endometriosis lesions and the presence of chronic pain. This research paper expands the presentation of our research at the World Endometriosis Congress in 2021, subsequently published in the Journal of Pain Research which demonstrated a strong inverse relationship between androgen levels and days per month of pelvic and period pain. Here we extend and further explore the evidence for a role for androgens in the etiology and management of dysmenorrhea and pelvic pain in women, both with and without endometriosis. We explore the potential for inflammation to induce low androgen levels and consider ways in which clinicians can optimize levels of androgens when treating women with these conditions. This article prompts the question: Is it estrogens that predispose people to a life of pain, or androgens that are protective?

Nitroxidative Signaling Mechanisms in Pathological Pain

Publisher: Elsevier BV

Date: 12-2016

DOI: 10.1016/J.TINS.2016.10.003

Perspective: Biomedical sensing and imaging with optical fibers - Innovation through convergence of science disciplines

Publisher: AIP Publishing

Date: 10-09-2018

DOI: 10.1063/1.5040861

Abstract: The probing of physiological processes in living organisms is a grand challenge that requires bespoke analytical tools. Optical fiber probes offer a minimally invasive approach to report physiological signals from specific locations inside the body. This perspective article discusses a wide range of such fiber probes developed at the Australian Research Council Centre of Excellence for Nanoscale BioPhotonics. Our fiber platforms use a range of sensing modalities, including embedded nanodiamonds for magnetometry, interferometric fiber cavities for refractive index sensing, and tailored metal coatings for surface plasmon resonance sensing. Other fiber probes exploit molecularly sensitive Raman scattering or fluorescence where optical fibers have been combined with chemical and immunosensors. Fiber imaging probes based on interferometry and computational imaging are also discussed as emerging in vivo diagnostic devices. We provide ex les to illustrate how the convergence of multiple scientific disciplines generates opportunities for the fiber probes to address key challenges in real-time in vivo diagnostics. These future fiber probes will enable the asking and answering of scientific questions that were never possible before.

The role of Toll‐like receptor 4 (TLR4) in cardiac ischaemic‐reperfusion injury, cardioprotection and preconditioning

Publisher: Wiley

Date: 26-07-2016

DOI: 10.1111/1440-1681.12602

Abstract: Cardiac ischaemic-reperfusion injury (IRI) remains the primary cause of mortality throughout the developed world. Molecular mechanisms underlying IRI are complex and are often interlinked with each other driving a synergistic response. Toll-like receptor 4 (TLR4), an immunosurveillance receptor, is known to enhance tissue injury during IRI by enhancing the inflammatory response. The release of endogenous components during IRI bind onto TLR4 leading to the activation of multiple signalling kinases. Once this event occurs these proteins are defined as danger associated molecular patterns molecules (DAMPs) or alarmins. Ex les include heat shock proteins, high mobility group box one (HMGB1) and extracellular matrix proteins, all of which are involved in IRI. However, literature in the last two decades suggests that transient stimulation of TLR4 may suppress IRI and thus improve cardiac recovery. Furthermore, it remains to be seen what role TLR4 plays during ischaemic-preconditioning where acute bouts of ischaemia, preceding a harmful bout of ischaemic-reperfusion, is cardioprotective. The other question which also needs to be considered is that if transient TLR4 signalling drives a preconditioning response then what are the ligands which drive this? Hence the second part of this review explores the possible TLR4 ligands which may promote cardioprotection against IRI.

Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth

Publisher: Springer Science and Business Media LLC

Date: 07-11-2016

DOI: 10.1038/SREP36112

Abstract: Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (−)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli . Local induction by E. coli of inflammatory cytokine genes Il1b , Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting.

The future: New concepts and potential therapies

Publisher: Cambridge University Press

Date: 07-11-2011

DOI: 10.1017/CBO9781139152211.030

Ibudilast reduces oxaliplatin-induced tactile allodynia and cognitive impairments in rats

Publisher: Elsevier BV

Date: 09-2017

DOI: 10.1016/J.BBR.2017.07.021

Abstract: Chemotherapy can cause serious neurotoxic side effects, such as painful peripheral neuropathies and disabling cognitive impairments. Four experiments examined whether Ibudilast, a clinically approved neuroimmune therapy, would reduce tactile allodynia and memory impairments caused by oxaliplatin in laboratory rats. Rats received an intraperitoneal injection of oxaliplatin (6mg/kg i.p.) or vehicle and were assessed for tactile allodynia 3 or 5days after injection, memory impairments in the novel object and novel location recognition tests 10-12days after injection, and fear conditioning 14days after injection. Ibudilast (7.5mg/kg) or vehicle was administered prior to oxaliplatin (Experiments 1 and 3) or prior to behavioural testing (Experiments 2 and 4). Ibudilast treatment prior to oxaliplatin prevented the development of tactile allodynia and memory impairments. Ibudilast treatment prior to behavioural testing reduced oxaliplatin-induced tactile allodynia, memory impairments, and impaired renewal of fear conditioning. These results suggest that Ibudilast could be an effective treatment against oxaliplatin-induced neuropathies and cognitive impairments.

Graded peripheral nerve injury creates mechanical allodynia proportional to the progression and severity of microglial activity within the spinal cord of male mice

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.BBI.2020.11.018

(+)-Naloxone, an Opioid-Inactive Toll-Like Receptor 4 Signaling Inhibitor, Reverses Multiple Models of Chronic Neuropathic Pain in Rats

Publisher: Elsevier BV

Date: 05-2012

DOI: 10.1016/J.JPAIN.2012.02.005

Gender inequality in publishing during the COVID-19 pandemic

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.BBI.2020.11.022

Toll-Like Receptor 4 Regulates Lipopolysaccharide-Induced Inflammation and Lactation Insufficiency in a Mouse Model of Mastitis1

Publisher: Oxford University Press (OUP)

Date: 05-2014

DOI: 10.1095/BIOLREPROD.114.117663

Abstract: Lactation mastitis is a debilitating inflammatory breast disease in postpartum women. Disease severity is associated with markers of inflammation rather than bacterial load, suggesting that immune-signaling pathways activated in the host are important in the disease pathology. The role of the innate pattern recognition receptor toll-like receptor 4 (TLR4) in progression and resolution of mastitislike disease was investigated in a mouse model. Lipopolysaccharide in Matrigel (10 μg/10 μl) was administered into the teat canal of lactating Tlr4 null mutant and wild-type mice to induce a localized area of inflammation. Mastitis induction resulted in a marked influx of RB6-positive neutrophils and F4/80-positive macrophages, which was higher in Tlr4(-/-) mice compared to wild-type mice. Tlr4 null mutation resulted in an altered immune-signaling fingerprint following induction of mastitis, with attenuated serum cytokines, including CXCL1, CCL2, interleukin 1 beta, and tumor necrosis factor alpha compared to wild-type mice. In both genotypes, the localized area of inflammation had resolved after 7 days, and milk protein was evident. However, the mammary glands of wild-type mice exhibited reduced capacity for milk production, with decreased percent area populated with glandular epithelium and decreased abundance of nuclear phosphorylated signal transducer and activator of transcription 5 compared to Tlr4 null mice. This study demonstrates that inflammatory pathways activated in the host are critically important in mastitis disease progression and suggests that lactation insufficiency associated with mastitis may be a consequence of TLR4-mediated inflammation, rather than the bacterial infection itself.

Low-dose endotoxin potentiates capsaicin-induced pain in man: Evidence for a pain neuroimmune connection

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.BBI.2013.03.002

Abstract: Despite the wealth of evidence in animals that immune activation has a key role in the development and maintenance of chronic pain, evidence to support this in humans is scant. We have sought such evidence by examining the effect of a subtle immunological stimulus, low dose intravenous endotoxin, on the allodynia, hyperalgesia, flare and pain produced by intradermal capsaicin in healthy volunteers. Here we provide evidence of immune priming of this neuropathic-like pain response in humans. Specifically, in 12 healthy volunteers, activation of Toll-Like Receptor 4 by endotoxin (0.4ng/kg IV) caused significant 5.1-fold increase in the 90-min integral of areas of capsaicin-induced allodynia (95% CI 1.3-9.1), 2.2-fold increase in flare (95% CI 1.9-2.6) and 1.8-fold increase in hyperalgesia (95% CI 1.1-2.5) following 50μg intradermal capsaicin injected into the forearm 3.5h after endotoxin. These data demonstrate clinically a significant role for the neuroimmune pain connection in modifying pain, thus providing evidence that immune priming may produce pain enhancement in humans and hence offer a novel range of pharmacological targets for anti-allodynics and/or analgesics. Additionally, the simplicity of the model makes it suitable as a test-bed for novel immune-targeted pain therapeutics.

Sphingosine-1-phosphate receptor subtype 1 activation in the central nervous system contributes to morphine withdrawal in rodents

Publisher: Springer Science and Business Media LLC

Date: 22-10-2020

DOI: 10.1186/S12974-020-01975-2

Abstract: Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1β (IL-1β) these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.

Visualizing neuroinflammation with fluorescence and luminescent lanthanide-based in situ hybridization

Publisher: Springer Science and Business Media LLC

Date: 21-03-2019

DOI: 10.1186/S12974-019-1451-2

Intrathecal implantation surgical considerations in rodents; a review

Publisher: Elsevier BV

Date: 11-2021

DOI: 10.1016/J.JNEUMETH.2021.109327

Measuring and tracking vitamin B12: A review of current methods with a focus on optical spectroscopy

Publisher: Informa UK Limited

Date: 13-09-2017

DOI: 10.1080/05704928.2016.1229325

Effect of Chronic Delivery of the Toll-like Receptor 4 Antagonist (+)-Naltrexone on Incubation of Heroin Craving

Publisher: Elsevier BV

Date: 04-2013

DOI: 10.1016/J.BIOPSYCH.2012.12.019

Inflammatory Mediators in Mastitis and Lactation Insufficiency

Publisher: Springer Science and Business Media LLC

Date: 25-06-2014

DOI: 10.1007/S10911-014-9325-9

Abstract: Mastitis is a common inflammatory disease during lactation that causes reduced milk supply. A growing body of evidence challenges the central role of pathogenic bacteria in mastitis, with disease severity associated with markers of inflammation rather than infection. Inflammation in the mammary gland may be triggered by microbe-associated molecular patterns (MAMPs) as well as danger-associated molecular patterns (DAMPs) binding to pattern recognition receptors such as the toll-like receptors (TLRs) on the surface of mammary epithelial cells and local immune cell populations. Activation of the TLR4 signalling pathway and downstream nuclear factor kappa B (NFkB) is critical to mediating local mammary gland inflammation and systemic immune responses in mouse models of mastitis. However, activation of NFkB also induces epithelial cell apoptosis and reduced milk protein synthesis, suggesting that inflammatory mediators activated during mastitis promote partial involution. Perturbed milk flow, maternal stress and genetic predisposition are significant risk factors for mastitis, and could lead to a heightened TLR4-mediated inflammatory response, resulting in increased susceptibility and severity of mastitis disease in the context of low MAMP abundance. Therefore, heightened host inflammatory signalling may act in concert with pathogenic or commensal bacterial species to cause both the inflammation associated with mastitis and lactation insufficiency. Here, we present an alternate paradigm to the widely held notion that breast inflammation is driven principally by infectious bacterial pathogens, and suggest there may be other therapeutic strategies, apart from the currently utilised antimicrobial agents, that could be employed to prevent and treat mastitis in women.

A Method for in vivo quantification of cytokine IL-1β in the rat intrathecal space

Publisher: American Chemical Society (ACS)

Date: 16-12-2020

DOI: 10.1021/ACSABM.9B00958

Abstract: IL-1β is a potent pro-inflammatory cytokine critical to multiple pathologies in the central nervous system (CNS). Quantification of IL-1β in vivo is challenging due to pM range of IL-1β released in the spinal cord and also the terminal nature of cerebrospinal fluid (CSF) s ling in rodents. Herein we developed a robust in vivo device on stainless steel suitable for detection of IL-1β in the spinal cord of rats. This approach offers high sensitivity (3.2 pg mL

'Convergence' created psychoneuroimmunology, and is needed again to secure the future of the field.

Publisher: Elsevier BV

Date: 07-2018

DOI: 10.1016/J.BBI.2018.05.011

Local and Systemic Inflammation in Localized, Provoked Vestibulodynia

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-2016

DOI: 10.1097/AOG.0000000000001510

Abstract: To synthesize and critically evaluate all available evidence investigating whether localized, provoked vestibulodynia is associated with a specific inflammatory profile at both a local and a systemic level. Comprehensive electronic searches were performed in MEDLINE, EMBASE, Scopus, PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Collaboration databases, and ClinicalTrials.gov. The search strategy was developed using MeSH terms related to localized, provoked vestibulodynia, and inflammatory markers. Two independent investigators screened titles and abstracts and performed data extraction and risk of bias assessments. Studies were included if they reported at least one baseline inflammatory marker in women with localized, provoked vestibulodynia and compared them with healthy women. Reference lists from published reviews on localized, provoked vestibulodynia were screened for additional studies. There were 1,619 studies identified. Eighteen studies met the inclusion criteria, including 400 women with localized, provoked vestibulodynia and 212 healthy women in a control group. Risk of bias assessment revealed that the methodologic quality was generally low. Fifteen studies investigated local inflammation and three studies investigated systemic inflammation. On a local level, the number of mast cells expressed in vestibular tissues was greater in women with localized, provoked vestibulodynia expressed than in women in the control group. Several studies reported undefined inflammatory infiltrate in vestibular tissues to a greater level in women with localized, provoked vestibulodynia than in women in the control group. Systemically, levels of natural killer cells were lower in women with localized, provoked vestibulodynia than in women in the control group. There were no systemic differences in systemic interferon-α and interferon-ϒ levels between groups. There is limited and contradictory evidence regarding the characteristics of local and systemic inflammation in women with localized, provoked vestibulodynia.

Ethnicity-dependent influence of innate immune genetic markers on morphine PCA requirements and adverse effects in postoperative pain

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 14-07-2016

DOI: 10.1097/J.PAIN.0000000000000661

Abstract: Although several genetic factors have been associated with postsurgical morphine requirements, those involving the innate immune system and cytokines have not been well investigated. The aim of this study was to investigate the contribution of genetic variability in innate immune signalling pathways to variability in morphine dosage after elective caesarean section under spinal anaesthesia in 133 Indian, 230 Malay, and 598 Han Chinese women previously studied. Twenty single nucleotide polymorphisms in 14 genes involved in glial activation ( TLR2 , TLR4 , MYD88 , MD2 ), inflammatory signalling ( IL2, IL6, IL10, IL1B, IL6R, TNFA , TGFB1, CRP, CASP1 ), and neuronal regulation ( BDNF ) were newly investigated, in addition to OPRM1 , COMT , and ABCB1 genetic variability identified previously. Postsurgical patient-controlled analgesia morphine use (mg/24 hours) was binned into 6 normally distributed groups and scored 0 to 5 to facilitate step-down multiple linear regression analysis of genetic predictors, controlling for ethnicity and nongenetic variables. Ethnicity, OPRM1 rs1799971 (increased), TLR2 rs3804100 (decreased), and an interaction between ethnicity and IL1B rs1143634 (increased), predicted 9.8% of variability in morphine use scores in the entire cohort. In the Indian cohort, 14.5% of the variance in morphine use score was explained by IL1B rs1143634 (increased) and TGFB1 rs1800469 (decreased). In Chinese patients, the incidence of postsurgical pain was significantly higher in variant COMT rs4680 genotypes ( P = 0.0007) but not in the Malay or Indian cohorts. Innate immune genetics may contribute to variability in postsurgical opioid requirements in an ethnicity-dependent manner.

Improved method for optical fiber temperature probe implantation in brains of free-moving rats

Publisher: Elsevier BV

Date: 02-2019

DOI: 10.1016/J.JNEUMETH.2018.12.013

Abstract: The localized monitoring of brain temperature is crucial to the understanding of the mechanisms underlying brain hyperthermia, such as that caused by stimulant drugs. Many animal studies investigating brain hyperthermia have utilized thermocouple electrodes for temperature measurement, however optical fiber sensors have proven to be an attractive alternative to conventional measurement techniques. Despite their advantages, optical fiber sensors in their current form have struggled to find effective use in studies involving free-moving animals. We have developed an improved optical fiber temperature probe and implantation method suitable for sensing in free-moving animals. By altering the structure of the probe, conventional guide cannulae can be used for stereotaxic implantation thus increasing ease-of-use and probe durability. The new probe structure was easily implanted and extremely durable both pre-experimentation and during s ling in vivo. Probe re-usability also allowed for increased experimental workflow. Rats administered MDMA showed pathological increases in brain temperature. Thermocouples commonly used for temperature measurement in deep brain structures lack the advantages offered by optical fiber sensors. Unlike our improved design, previous optical fiber temperature probes were unable to be removed from the brains of rats without removing the dental cement affixing it to the skull. This made the probe susceptible to breakage and often resulted in the complete loss of the animal from the experiment. Our fiber temperature probe and revised implantation technique can be easily employed in brain thermorecording using advantageous optical fiber sensors suitable for use in awake free-moving animals.

Naloxone-precipitated morphine withdrawal behavior and brain IL-1β expression: Comparison of different mouse strains

Publisher: Elsevier BV

Date: 08-2011

DOI: 10.1016/J.BBI.2011.03.016

Pulmonary hypertension and pregnancy outcomes: data from the Registry Of Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology

Publisher: Wiley

Date: 07-07-2016

DOI: 10.1002/EJHF.594

Abstract: To describe the outcomes of pregnancy in women with pulmonary hypertension. In 2007 the European Registry on Pregnancy and Heart Disease was initiated by the European Society of Cardiology. Consecutive patients with all forms of cardiovascular disease, presenting with pregnancy, were enrolled with the aim of investigating the pregnancy outcomes. This subgroup of the cohort included 151 women with pulmonary hypertension (PH) either diagnosed by right heart catheterization or diagnosed as possible PH by echocardiographic signs, with 26% having pulmonary arterial hypertension (PAH), in three subgroups: idiopathic (iPAH), associated with congenital heart disease (CHD-PAH), or associated with other disease (oPAH), and 74% having PH caused by left heart disease (LHD-PH, n = 112). Maternal mean age was 29.2 ± 5.6 years and 37% were nulliparous. Right ventricular systolic pressure was 70 mmHg in 11.9%. In more than 75% of patients, the diagnosis of PH had been made before pregnancy. Maternal death up to 1 week after delivery occurred in five patients (3.3%), with another two out of 78 patients who presented for follow-up (2.6%), dying within 6 months after delivery. The highest mortality was found in iPAH (3/7, 43%). During pregnancy, heart failure occurred in 27%. Caesarean section was performed in 63.4% (23.9% as emergency). Therapeutic abortion was performed in 4.0%. Complications included miscarriage (5.6%), fetal mortality (2%), premature delivery (21.7%), low birth weight (19.0%), and neonatal mortality (0.7%). Mortality in this group of patients with various forms of PH was lower than previously reported as specialized care during pregnancy and delivery was available. However, maternal and fetal mortality remains prohibitively high in women with iPAH, although this conclusion is restricted by limited numbers. Early advice on contraception, pregnancy risk and fetal outcome remains paramount.

Glial-modulating agents for the treatment of pain: protocol for a systematic review

Publisher: BMJ

Date: 04-2022

DOI: 10.1136/BMJOPEN-2021-055713

Abstract: Evidence suggests a role for Central nervous system glia in pain transmission and in augmenting maladaptive opioid effects. Identification of drugs that modulate glia has guided the evaluation of glial suppression as a pain management strategy. This planned systematic review will describe evidence of the efficacy and adverse effects of glial-modulating drugs in pain management. A detailed search will be conducted on the Cochrane Central Register of Controlled Trials, Medline, and Embase from their inception until the date the final searches are run to identify relevant randomised controlled trials. The reference lists of retrieved studies, as well as online trial registries, will also be searched. English language, randomised, double-blind trials comparing various glial-modulating drugs with placebo and/or other comparators, with participant-reported pain assessment, will be included. Two reviewers will independently evaluate studies for eligibility, extract data and assess trial quality and potential bias. Risk of bias will be assessed using criteria outlined in the Cochrane Handbook for Systematic Review of Interventions . Primary outcomes for this review will include any validated measure of pain intensity and/or pain relief. Dichotomous data will be used to calculate risk ratio and number needed to treat or harm. The quality of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation. This systematic review does not require formal ethics approval. The findings will be disseminated through peer-reviewed publications and conference presentations. CRD42021262074.

Are the protective benefits of vitamin D in neurodegenerative disease dependent on route of administration? A systematic review

Publisher: Informa UK Limited

Date: 09-07-2018

DOI: 10.1080/1028415X.2018.1493807

A novel animal model of graded neuropathic pain: Utility to investigate mechanisms of population heterogeneity

Publisher: Elsevier BV

Date: 10-2010

DOI: 10.1016/J.JNEUMETH.2010.08.025

Abstract: The mechanisms underlying neuropathic pain are not well understood, resulting in unsatisfactory treatment outcomes for many patients. Animal models underpin much of the current understanding of pain mechanisms due to their perceived ability to mimic pain hypersensitivities however, are limited by their binomial approach (pain vs. control), which does not reflect the clinical heterogeneity in nociceptive hypersensitivity. We modified the chronic constriction injury model by varying the number of sciatic nerve chromic gut sutures. Each Sprague Dawley rat received 4 pieces of chromic gut to control for the inflammatory challenge posed by the gut. Treatment groups were neuronal sutures (N), subcutaneous sutures (S) N0S0, N0S4, N1S3, N2S2 and N4S0. At postoperative (PO) day 29, there was a 'dose-response' relationship between the number of perineural sutures and von Frey threshold (N0S4<N1S3<N2S2<N4S0, P<0.05). This graded model was applied to investigate lumbar dorsal spinal cord glial activation marker expression. Microglial CD11b expression was positively correlated with graded allodynia in the ipsilateral dorsal horn (P 0.9) and associated in the dorsolateral funiculus (DLF P=0.10, r(2)>0.8) at PO day 14. Astrocyte GFAP expression was positively associated with graded allodynia in the ipsilateral dorsal horn (P=0.18, r(2)>0.6) and ipsilateral DLF (P 0.9). DLF glial activation may represent a contributor to contralateral pain. Our novel graded model has a dynamic range, allowing sensitive detection of interactions and subtle influences on neuropathic pain processing.

Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-P

Publisher: Oxford University Press (OUP)

Date: 22-03-2017

DOI: 10.1093/EURHEARTJ/EHW593

Glial Attenuation With Ibudilast in the Treatment of Medication Overuse Headache: A Double‐Blind, Randomized, Placebo‐Controlled Pilot Trial of Efficacy and Safety

Publisher: Wiley

Date: 14-09-2015

DOI: 10.1111/HEAD.12655

Abstract: Medication overuse headache (MOH) is a condition bordering between a chronic pain condition and a substance dependence disorder. Activation of immunocompetent glial cells in the central nervous system has been linked to both pathological pain and drug addiction/reward. Preclinically, ibudilast attenuates glial activation and is able to reduce neuropathic pain and markers of substance dependence. We therefore hypothesized ibudilast would reduce headache burden and opioid analgesic requirements in patients with opioid overuse headache. To determine if treatment with ibudilast provides a greater reduction in headache index than placebo in MOH patients consuming opioids. Participants with MOH who were using opioids were randomized via computer-generated code to ibudilast 40 mg or placebo twice daily for 8 weeks in a double-blind, parallel groups study. Before randomization participants completed a 4-week baseline headache diary. During treatment, headache diary data collection continued and participants attended 4 study visits during which quantitative sensory testing was performed. Blood s les for immune biomarker analyses were collected before and after treatment in a subgroup of participants. Thirty-four participants were randomized, 13 of 15 randomized to ibudilast and 17 of 19 randomized to placebo completed treatment. Ibudilast was generally well-tolerated with mild, transient nausea reported as the most common adverse event (66.7% vs 10.5% in placebo group). Results are shown as mean (SD). At the end of treatment no differences in the primary outcome average daily headache index (placebo 62 [44] vs ibudilast 77 [72] groups, difference -15, CI -65 to 35 h × numerical rating scale), or secondary outcomes headache frequency (placebo 23 [8.1] vs ibudilast 24.5 [6.2], difference -1.5, CI -7.7 to 4.8 days/month) and opioid intake (placebo 20.6 [43] vs ibudilast 19 [24.3], difference 1.6, CI -31.5 to 34.8 mg morphine equivalent) were observed between placebo and ibudilast groups. Using the current dosing regimen, ibudilast does not improve headache or reduce opioid use in patients with MOH without mandated opioid withdrawal. However, it would be of interest to determine in future trials if ibudilast is able to improve ease of withdrawal during a forced opioid down-titration when incorporated into an MOH detoxification program.

Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder

Publisher: Frontiers Media SA

Date: 30-09-2014

DOI: 10.3389/FNINS.2014.00309

Neuroimmune reactivity marker expression in rodent models of chemotherapy-induced cognitive impairment: A systematic scoping review

Publisher: Elsevier BV

Date: 05-2021

DOI: 10.1016/J.BBI.2021.01.021

Challenges and opportunities in neurophotonics discussed at the International Conference on Biophotonics 2017

Publisher: SPIE-Intl Soc Optical Eng

Date: 30-10-2018

DOI: 10.1117/1.NPH.5.4.040402

Mortality Benefit of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary or Peripheral Artery Disease

Publisher: Elsevier BV

Date: 07-2021

DOI: 10.1016/J.JACC.2021.04.083

Hollow-Core Optical Fibers Made by Glass Billet Extrusion as Sensors for Raman Spectroscopy

Publisher: OSA

Date: 2016

DOI: 10.1364/ACOFT.2016.AM3C.3

Effects of Mild and Moderate Monoclonal Antibody Dose on Inflammation, Bone Loss, and Activation of the Central Nervous System in a Female Collagen Antibody-induced Arthritis Mouse Model

Publisher: SAGE Publications

Date: 22-07-2021

DOI: 10.1369/00221554211033562

Abstract: Induction of severe inflammatory arthritis in the collagen antibody-induced arthritis (CAIA) murine model causes extensive joint damage and pain-like behavior compromising analysis. While mild models are less severe, their reduced, variable penetrance makes assessment of treatment efficacy difficult. This study aimed to compare macroscopic and microscopic changes in the paws, along with central nervous system activation between a mild and moderate CAIA model. Balb/c mice ( n=18) were allocated to control, mild, and moderate CAIA groups. Paw inflammation, bone volume (BV), and paw volume (PV) were assessed. Histologically, the front paws were assessed for joint inflammation, cartilage damage, and pre/osteoclast-like cells and the lumbar spinal cord and the periaqueductal gray (PAG) region of the brain for glial reactivity. A moderate CAIA dose induced (1) significantly greater local paw inflammation, inflammatory cell infiltration, and PV (2) significantly more osteoclast-like cells on the bone surface and within the surrounding soft tissue and (3) significantly greater glial reactivity within the PAG compared with the mild CAIA model. These findings support the use of a moderate CAIA model (higher dose of monoclonal antibodies with low-dose lipopolysaccharide) to induce more consistent histopathological features, without excessive joint destruction.

Stereochemistry and innate immune recognition: (+)‐norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll‐like receptor 4 signaling

Publisher: Wiley

Date: 04-06-2019

DOI: 10.1096/FJ.201900173RRR

Multi-coloured fluorescent sensing toolbox for selective detection of nitroxyl in vitro and ex vivo

Publisher: Royal Society of Chemistry (RSC)

Date: 2022

DOI: 10.1039/D2SD00006G

Abstract: Methods for the endogenous detection of nitroxyl (azanone HNO), the reduced and protonated derivative of nitric oxide (NO), are required to define its cardiovascular function and its key role in chronic pain.

Commentary on Landry et al.: “Propentofylline, a CNS glial modulator, does not decrease pain in post-herpetic neuralgia patients: In vitro evidence for differential responses in human and rodent micro

Publisher: Elsevier BV

Date: 04-2012

DOI: 10.1016/J.EXPNEUROL.2012.01.006

The Neuroimmunology of Chronic Pain: From Rodents to Humans

Publisher: Society for Neuroscience

Date: 25-11-2020

DOI: 10.1523/JNEUROSCI.1650-20.2020

Abstract: Chronic pain, encompassing conditions, such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders, is highly prevalent but remains poorly treated. The vast majority of therapeutics are directed solely at neurons, despite the fact that signaling between immune cells, glia, and neurons is now recognized as indispensable for the initiation and maintenance of chronic pain. This review highlights recent advances in understanding fundamental neuroimmune signaling mechanisms and novel therapeutic targets in rodent models of chronic pain. We further discuss new technological developments to study, diagnose, and quantify neuroimmune contributions to chronic pain in patient populations.

A concern on comparing ‘apples’ and ‘oranges’ when differences between microglia used in human and rodent studies go far, far beyond simply species: comment on Smith and Dragunow

Publisher: Elsevier BV

Date: 04-2014

DOI: 10.1016/J.TINS.2014.02.004

Prevalence, outcomes and costs of a contemporary, multinational population with heart failure

Publisher: BMJ

Date: 13-02-2023

DOI: 10.1136/HEARTJNL-2022-321702

Abstract: Digital healthcare systems could provide insights into the global prevalence of heart failure (HF). We designed the CardioRenal and Metabolic disease (CaReMe) HF study to estimate the prevalence, key clinical adverse outcomes and costs of HF across 11 countries. In idual level data from a contemporary cohort of 6 29 624 patients with diagnosed HF was obtained from digital healthcare systems in participating countries using a prespecified, common study plan, and summarised using a random effects meta-analysis. A broad definition of HF (any registered HF diagnosis) and a strict definition (history of hospitalisation for HF) were used. Event rates were reported per 100 patient years. Cumulative hospital care costs per patient were calculated for a period of up to 5 years. The prevalence of HF was 2.01% (95% CI 1.65 to 2.36) and 1.05% (0.85 to 1.25) according to the broad and strict definitions, respectively. In patients with HF (broad definition), mean age was 75.2 years (95% CI 74.0 to 76.4), 48.8% (40.9–56.8%) had ischaemic heart disease and 34.5% (29.4–39.6%) had diabetes. In 51 442 patients with a recorded ejection fraction (EF), 39.1% (30.3–47.8%) had a reduced, 18.8% (13.5–24.0%) had a mildly reduced and 42.1% (31.5–52.8%) had a preserved left ventricular EF. In 1 69 518 patients with recorded estimated glomerular filtration rate, 49% had chronic kidney disease (CKD) stages III–V. Event rates were highest for cardiorenal disease (HF or CKD) and all cause mortality (19.3 (95% CI 11.3 to 27.1) and 13.1 (11.1 to 15.1), respectively), and lower for myocardial infarction, stroke and peripheral artery disease. Hospital care costs were highest for cardiorenal diseases. We estimate that 1–2% of the contemporary adult population has HF. These in iduals are at significant risk of adverse outcomes and associated costs, predominantly driven by hospitalisations for HF or CKD. There is considerable public health potential in understanding the contemporary burden of HF and the importance of optimising its management.

European Society of Cardiology: Cardiovascular Disease Statistics 2019

Publisher: Oxford University Press (OUP)

Date: 10-12-2019

DOI: 10.1093/EURHEARTJ/EHZ859

Abstract: The 2019 report from the European Society of Cardiology (ESC) Atlas provides a contemporary analysis of cardiovascular disease (CVD) statistics across 56 member countries, with particular emphasis on international inequalities in disease burden and healthcare delivery together with estimates of progress towards meeting 2025 World Health Organization (WHO) non-communicable disease targets. In this report, contemporary CVD statistics are presented for member countries of the ESC. The statistics are drawn from the ESC Atlas which is a repository of CVD data from a variety of sources including the WHO, the Institute for Health Metrics and Evaluation, and the World Bank. The Atlas also includes novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery obtained by annual survey of the national societies of ESC member countries. Across ESC member countries, the prevalence of obesity (body mass index ≥30 kg/m2) and diabetes has increased two- to three-fold during the last 30 years making the WHO 2025 target to halt rises in these risk factors unlikely to be achieved. More encouraging have been variable declines in hypertension, smoking, and alcohol consumption but on current trends only the reduction in smoking from 28% to 21% during the last 20 years appears sufficient for the WHO target to be achieved. The median age-standardized prevalence of major risk factors was higher in middle-income compared with high-income ESC member countries for hypertension {23.8% [interquartile range (IQR) 22.5–23.1%] vs. 15.7% (IQR 14.5–21.1%)}, diabetes [7.7% (IQR 7.1–10.1%) vs. 5.6% (IQR 4.8–7.0%)], and among males smoking [43.8% (IQR 37.4–48.0%) vs. 26.0% (IQR 20.9–31.7%)] although among females smoking was less common in middle-income countries [8.7% (IQR 3.0–10.8) vs. 16.7% (IQR 13.9–19.7%)]. There were associated inequalities in disease burden with disability-adjusted life years per 100 000 people due to CVD over three times as high in middle-income [7160 (IQR 5655–8115)] compared with high-income [2235 (IQR 1896–3602)] countries. Cardiovascular disease mortality was also higher in middle-income countries where it accounted for a greater proportion of potential years of life lost compared with high-income countries in both females (43% vs. 28%) and males (39% vs. 28%). Despite the inequalities in disease burden across ESC member countries, survey data from the National Cardiac Societies of the ESC showed that middle-income member countries remain severely under-resourced compared with high-income countries in terms of cardiological person-power and technological infrastructure. Under-resourcing in middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, device implantation and cardiac surgical procedures. A seemingly inexorable rise in the prevalence of obesity and diabetes currently provides the greatest challenge to achieving further reductions in CVD burden across ESC member countries. Additional challenges are provided by inequalities in disease burden that now require intensification of policy initiatives in order to reduce population risk and prioritize cardiovascular healthcare delivery, particularly in the middle-income countries of the ESC where need is greatest.

Early-Life Experience Decreases Drug-Induced Reinstatement of Morphine CPP in Adulthood via Microglial-Specific Epigenetic Programming of Anti-Inflammatory IL-10 Expression

Publisher: Society for Neuroscience

Date: 07-12-2011

DOI: 10.1523/JNEUROSCI.3297-11.2011

Abstract: A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat nucleus accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene × early-life environment interaction on morphine-induced glial activation and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior.

Study design and rationale for the Stabilization of pLaques usIng Darapladib—Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome

Publisher: Elsevier BV

Date: 10-2011

DOI: 10.1016/J.AHJ.2011.07.018

Abstract: Higher levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with a higher risk of cardiovascular events and may play a causal role in atherogenesis. Darapladib inhibits Lp-PLA(2) activity in plasma and in arterial plaques and may confer clinical benefit in preventing cardiovascular events. The SOLID-TIMI 52 trial is a randomized, double-blind, placebo-controlled, multicenter, event-driven trial. Approximately 13,000 subjects are being randomized to darapladib (160 mg enteric-coated tablet daily) or matching placebo within 30 days of hospitalization with an acute coronary syndrome. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points include major and total coronary events, in idual components of the primary end point, and all-cause mortality. The study will continue until approximately 1,500 primary end point events have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be approximately 3 years, with a total study duration of approximately 4.1 years. The SOLID-TIMI 52 trial will determine the clinical benefit of direct inhibition of Lp-PLA(2) activity with darapladib in patients after an acute coronary syndrome.

Toll-Like Receptor 4 in Pain: Bridging Molecules-to-Cells-to-Systems

Publisher: Springer International Publishing

Date: 2022

DOI: 10.1007/164_2022_587

Abstract: Pain impacts the lives of billions of people around the world - both directly and indirectly. It is complex and transcends beyond an unpleasant sensory experience to encompass emotional experiences. To date, there are no successful treatments for sufferers of chronic pain. Although opioids do not provide any benefit to chronic pain sufferers, they are still prescribed, often resulting in more complications such as hyperalgesia and dependence. In order to develop effective and safe medications to manage, and perhaps even treat pain, it is important to evaluate novel contributors to pain pathologies. As such, in this chapter we review the role of Toll-like receptor 4, a receptor of the innate immune system, that continues to gain substantial attention in the field of pain research. Positioned in the nexus of the neuro and immune systems, TLR4 may provide one of the missing pieces in understanding the complexities of pain. Here we consider how TLR4 enables a mechanistical understanding of pain as a multidimensional biopsychosocial state from molecules to cells to systems and back again.

Measurements of vitamin B12 in human blood serum using resonance Raman spectroscopy

Publisher: IEEE

Date: 10-2017

DOI: 10.1109/IPCON.2016.7831287

Guía de práctica clínica de la ESC para el manejo del infarto agudo de miocardio en pacientes con elevación del segmento ST

Publisher: Elsevier BV

Date: 2013

DOI: 10.1016/J.RECESP.2012.10.014

Drug addiction: targeting dynamic neuroimmune receptor interactions as a potential therapeutic strategy

Publisher: Elsevier BV

Date: 02-2016

DOI: 10.1016/J.COPH.2015.10.010

Abstract: Drug addiction and dependence have proven to be difficult psychiatric disorders to treat. The limited efficacy of neuronally acting medications, such as ac rosate and naltrexone, highlights the need to identify novel targets. Recent research has underscored the importance of the neuroimmune system in many behavioural manifestations of drug addiction. In this review, we propose that our appreciation for complex phenotypes such as drug addiction and dependence will come with a greater understanding that these disorders are the result of intricate, interconnected signalling pathways that are, if only partially, determined at the receptor level. The idea of receptor heteromerisation and receptor mosaics will be introduced to explain cross talk between the receptors and signalling molecules implicated in neuroimmune signalling pathways.

Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia

Publisher: Elsevier BV

Date: 11-2008

DOI: 10.1016/J.BBI.2008.07.008

Acute stress induces the rapid and transient induction of caspase-1, gasdermin D and release of constitutive IL-1β protein in dorsal hippocampus

Publisher: Elsevier BV

Date: 11-2020

DOI: 10.1016/J.BBI.2020.07.042

Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1β

Publisher: Elsevier BV

Date: 2010

DOI: 10.1016/J.NEUROSCIENCE.2009.10.011

Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial

Publisher: Springer Science and Business Media LLC

Date: 12-05-2020

DOI: 10.1186/S13063-020-4202-X

Abstract: Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression. Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40–80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory). Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger s le size in a definitive phase 2 trial. ClinicalTrails.gov, NCT03589014 . Retrospectively registered on 17 July 2018.

Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES)

Publisher: Wiley

Date: 24-07-2014

DOI: 10.1002/EJHF.135

Abstract: The clinical outcomes for patients with worsening chronic heart failure (WCHF) remain exceedingly poor despite contemporary evidence-based therapies, and effective therapies are urgently needed. Accumulating evidence supports augmentation of cyclic guanosine monophosphate (cGMP) signalling as a potential therapeutic strategy for HF with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively). Direct soluble guanylate cyclase (sGC) stimulators target reduced cGMP generation due to insufficient sGC stimulation and represent a promising method for cGMP enhancement. The phase II SOluble guanylate Cyclase stimulatoR in heArT failurE Study (SOCRATES) programme consists of two randomized, parallel-group, placebo-controlled, double-blind, multicentre studies, SOCRATES-REDUCED (in patients with LVEF <45%) and SOCRATES-PRESERVED (in those with LVEF ≥ 45%), that will explore the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the once-daily oral sGC stimulator vericiguat (BAY 1021189) over 12 weeks compared with placebo. These studies will enrol patients stabilized during hospitalization for HF at the time of discharge or within 4 weeks thereafter. The primary endpoint in SOCRATES-REDUCED is change in NT-proBNP at 12 weeks. The primary endpoints in SOCRATES-PRESERVED are change in NT-proBNP and left atrial volume at 12 weeks. SOCRATES will be the first programme to enrol specifically both inpatients and outpatients with WCHF and patients with reduced or preserved ejection fraction. Results will inform the benefits of pursuing subsequent event-driven clinical outcome trials with sGC stimulators in this patient population.

Hyperspectral imaging of endogenous fluorescent metabolic molecules to identify pain states in central nervous system tissue

Publisher: SPIE

Date: 09-12-2016

DOI: 10.1117/12.2243158

Methamphetamine Activates Toll-Like Receptor 4 to Induce Central Immune Signaling within the Ventral Tegmental Area and Contributes to Extracellular Dopamine Increase in the Nucleus Accumbens Shell

Publisher: American Chemical Society (ACS)

Date: 08-07-2019

DOI: 10.1021/ACSCHEMNEURO.9B00225

DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling

Publisher: Springer Science and Business Media LLC

Date: 03-02-2015

DOI: 10.1038/MP.2014.177

The effects of pregabalin and the glial attenuator minocycline on the response to intradermal capsaicin in patients with unilateral sciatica

Publisher: Public Library of Science (PLoS)

Date: 07-06-2012

DOI: 10.1371/JOURNAL.PONE.0038525

Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain

Publisher: Elsevier BV

Date: 10-2011

DOI: 10.1016/J.BBI.2011.04.003

Abstract: Recent evidence implicates an adaptive immune response in the central nervous system (CNS) mechanisms of neuropathic pain. This review identifies how neuropathic pain alters CNS immune privilege to facilitate T cell infiltration. Once in the CNS, T cells may interact with the local antigen presenting cells, microglia, via the major histocompatibility complex and the costimulatory molecules CD40 and B7. In this way, T cells may contribute to the maintenance of neuropathic pain through pro-inflammatory interactions with microglia and by facilitating the activation of astrocytes in the spinal dorsal horn. Based on the evidence presented in this review, we suggest that this bidirectional, pro-inflammatory system of neurons, glia and T cells in neuropathic pain should be renamed the pentapartite synapse, and identifies the latest member as a potential disease-modifying therapeutic target.

Ibudilast (AV-411)

Publisher: Informa Healthcare

Date: 26-06-2007

DOI: 10.1517/13543784.16.7.935

Abstract: The treatment of neuropathic pain is a major unresolved medical challenge. Present pharmacotherapies only have modest efficacy and numerous side effects. The use of opioid analgesics is additionally coupled with dependence and withdrawal syndromes. Ibudilast (AV-411) is a non-selective phosphodiesterase inhibitor that is also known to suppress glial cell activation. It has been used clinically for other indications with a good safety profile. As glial cell activation is considered to crucially contribute to neuropathic pain as well as opioid dependence and withdrawal, the authors conceived that ibudilast may be useful for treating these conditions. Preclinical data indicate that ibudilast crosses the blood-brain barrier, is well tolerated, is active on oral administration, reduces glial activation and attenuates pain symptoms in erse rat models of neuropathic pain. In addition, it enhances acute morphine analgesia and attenuates morphine tolerance and withdrawal. Thus ibudilast may improve opioid efficacy and is a promising therapeutic candidate for neuropathic pain, with a novel mechanism of action.

TLR4 biased small molecule modulators

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.PHARMTHERA.2021.107918

Abstract: Biased pharmacological modulators provide potential therapeutic benefits, including greater pharmacodynamic specificity, increased efficiency and reduced adverse effects. Therefore, the identification of such modulators as drug candidates is highly desirable. Currently, attention was mainly paid to biased signaling modulators targeting G protein-coupled receptors (GPCRs). The biased signaling modulation of non-GPCR receptors has yet to be exploited. Toll-like receptor 4 (TLR4) is one such non-GPCR receptor, which involves MyD88-dependent and TRIF-dependent signaling pathways. Moreover, the dysregulation of TLR4 contributes to numerous diseases, which highlights the importance of biased modulator development targeting TLR4. In this review, we aim to provide an overview of the recent progress in the discovery of biased modulators of TLR4. The challenges and methods for the discovery of TLR4 biased modulators are also outlined. Small molecules biasedly modulating the TLR4 signaling axis not only provide probes to fine-tune receptor conformation and signaling but also provide an opportunity to identify promising drug candidates. The discovery of biased modulators of TLR4 would provide insight for the future development of biased modulators for other non-GPCR receptors.

Reversible Protein Carbonylation In-Vivo Biosensor

Publisher: OSA

Date: 2019

DOI: 10.1364/SENSORS.2019.STU2D.3

TLR 2 and 4 responsiveness from isolated peripheral blood mononuclear cells from rats and humans as potential chronic pain biomarkers.

Publisher: Public Library of Science (PLoS)

Date: 30-10-2013

DOI: 10.1371/JOURNAL.PONE.0077799

First demonstration of the neuroimmune link in humans using IV Endotoxin and Intradermal Capsaicin in the face and arm

Publisher: No publisher found

DOI: 10.1186/1129-2377-14-S1-P221}

A Chat(GPT) about the future of scientific publishing

Publisher: Elsevier BV

Date: 05-2023

DOI: 10.1016/J.BBI.2023.02.022

An MD2 Hot‐Spot‐Mimicking Peptide that Suppresses TLR4‐Mediated Inflammatory Response in vitro and in vivo

Publisher: Wiley

Date: 15-06-2011

DOI: 10.1002/CBIC.201100211

The Neuroimmune Interface and Chronic Pain Through the Lens of Production Animals

Publisher: Frontiers Media SA

Date: 19-05-2022

DOI: 10.3389/FNINS.2022.887042

Abstract: Communication between the central nervous system (CNS) and the immune system has gained much attention for its fundamental role in the development of chronic and pathological pain in humans and rodent models. Following peripheral nerve injury, neuroimmune signaling within the CNS plays an important role in the pathophysiological changes in pain sensitivity that lead to chronic pain. In production animals, routine husbandry procedures such as tail docking and castration, often involve some degree of inflammation and peripheral nerve injury and consequently may lead to chronic pain. Our understanding of chronic pain in animals is limited by the difficulty in measuring this pathological pain state. In light of this, we have reviewed the current understanding of chronic pain in production animals. We discuss our ability to measure pain and the implications this has on animal welfare and production outcomes. Further research into the neuroimmune interface in production animals will improve our fundamental understanding of chronic pain and better inform human clinical pain management and animal husbandry practices and interventions.

Presentation, care, and outcomes of patients with NSTEMI according to World Bank country income classification: the ACVC-EAPCI EORP NSTEMI Registry of the European Society of Cardiology

Publisher: Oxford University Press (OUP)

Date: 03-02-2023

DOI: 10.1093/EHJQCCO/QCAD008

Abstract: The majority of NSTEMI burden resides outside high-income countries (HICs). We describe presentation, care, and outcomes of NSTEMI by country income classification. Prospective cohort study including 2947 patients with NSTEMI from 287 centres in 59 countries, stratified by World Bank country income classification. Quality of care was evaluated based on 12 guideline-recommended care interventions. The all-or-none scoring composite performance measure was used to define receipt of optimal care. Outcomes included in-hospital acute heart failure, stroke/transient ischaemic attack, and death, and 30-day mortality. Patients admitted with NSTEMI in low to lower-middle-income countries (LLMICs), compared with patients in HICs, were younger, more commonly diabetic, and current smokers, but with a lower burden of other comorbidities, and 76.7% met very high risk criteria for an immediate invasive strategy. Invasive coronary angiography use increased with ascending income classification (LLMICs, 79.2% upper middle income countries [UMICs], 83.7% HICs, 91.0%), but overall care quality did not (≥80% of eligible interventions achieved: LLMICS, 64.8% UMICs 69.6% HICs 55.1%). Rates of acute heart failure (LLMICS, 21.3% UMICs, 12.1% HICs, 6.8% P & 0.001), stroke/transient ischaemic attack (LLMICS: 2.5% UMICs: 1.5% HICs: 0.9% P = 0.04), in-hospital mortality (LLMICS, 3.6% UMICs: 2.8% HICs: 1.0% P & 0.001) and 30-day mortality (LLMICs, 4.9% UMICs, 3.9% HICs, 1.5% P & 0.001) exhibited an inverse economic gradient. Patients with NSTEMI in LLMICs present with fewer comorbidities but a more advanced stage of acute disease, and have worse outcomes compared with HICs. A cardiovascular health narrative is needed to address this inequity across economic boundaries.

Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial

Publisher: Elsevier BV

Date: 08-2019

DOI: 10.1053/J.GASTRO.2019.04.041

Abstract: Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk. We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation. There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88 95% confidence interval [CI], 0.67-1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52 95% confidence interval, 0.28-0.94 P = .03) this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45 95% confidence interval, 0.27-0.74), although the number needed to treat still was high (n = 982 95% confidence interval, 609-2528). In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials.gov ID: NCT01776424.

Pathological pain and the neuroimmune interface

Publisher: Springer Science and Business Media LLC

Date: 28-02-2014

DOI: 10.1038/NRI3621

Novel imaging tools for investigating the role of immune signalling in the brain

Publisher: Elsevier BV

Date: 11-2016

DOI: 10.1016/J.BBI.2016.04.014

Abstract: The importance of neuro-immune interactions in both physiological and pathophysiological states cannot be overstated. As our appreciation for the neuroimmune nature of the brain and spinal cord grows, so does our need to extend the spatial and temporal resolution of our molecular analysis techniques. Current imaging technologies applied to investigate the actions of the neuroimmune system in both health and disease states have been adapted from the fields of immunology and neuroscience. While these classical techniques have provided immense insight into the function of the CNS, they are however, inherently limited. Thus, the development of innovative methods which overcome these limitations are crucial for imaging and quantifying acute and chronic neuroimmune responses. Therefore, this review aims to convey emerging novel and complementary imaging technologies in a form accessible to medical scientists engaging in neuroimmune research.

200 Chemotherapy Induces Intestinal Inflammation and Central Changes Which Are Modified by Analgesics via Neuro-Immune Mechanisms

Publisher: Elsevier BV

Date: 04-2016

DOI: 10.1016/S0016-5085(16)30301-8

Rationale, design, and baseline participant characteristics in the MRI and cognitive substudy of the cardiovascular outcomes for people using anticoagulation strategies trial

Publisher: SAGE Publications

Date: 30-07-2018

DOI: 10.1177/1747493018784478

Abstract: Covert vascular disease of the brain manifests as infarcts, white matter hyperintensities, and microbleeds on MRI. Their cumulative effect is often a decline in cognition, motor impairment, and psychiatric disorders. Preventive therapies for covert brain ischemia have not been established but represent a huge unmet clinical need. The MRI substudy examines the effects of the antithrombotic regimens in COMPASS on incident covert brain infarcts (the primary outcome), white matter hyperintensities, and cognitive and functional status in a s le of consenting COMPASS participants without contraindications to MRI. COMPASS is a randomized superiority trial testing rivaroxaban 2.5 mg bid plus acetylsalicylic acid 100 mg and rivaroxaban 5 mg bid against acetylsalicylic acid 100 mg per day for the combined endpoint of MI, stroke, and cardiovascular death in in iduals with stable coronary artery disease or peripheral artery disease. T1-weighted, T2-weighted, T2*-weighted, and FLAIR images were obtained close to randomization and near the termination of assigned antithrombotic therapy biomarker and genetic s les at randomization and one month, and cognitive and functional assessment at randomization, after two years and at the end of study. Between March 2013 and May 2016, 1905 participants were recruited from 86 centers in 16 countries. Of these participants, 1760 underwent baseline MRI scans that were deemed technically adequate for interpretation. The mean age at entry of participants with interpretable MRI was 71 years and 23.5% were women. Coronary artery disease was present in 90.4% and 28.1% had peripheral artery disease. Brain infarcts were present in 34.8%, 29.3% had cerebral microbleeds, and 93.0% had white matter hyperintensities. The median Montreal Cognitive Assessment score was 26 (interquartile range 23–28). The COMPASS MRI substudy will examine the effect of the antithrombotic interventions on MRI-determined covert brain infarcts and cognition. Demonstration of a therapeutic effect of the antithrombotic regimens on brain infarcts would have implications for prevention of cognitive decline and provide insight into the pathogenesis of vascular cognitive decline.

Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury

Publisher: Elsevier BV

Date: 11-2016

DOI: 10.1016/J.BBI.2016.08.004

Relationship between 4,5-epoxymorphinan structure and in vitro modulation of cell proliferation

Publisher: Elsevier BV

Date: 06-2004

DOI: 10.1016/J.EJPHAR.2004.04.049

Portable optical fiber probe for in vivo brain temperature measurements

Publisher: The Optical Society

Date: 20-07-2016

DOI: 10.1364/BOE.7.003069

Diacetylmorphine degradation to 6-monoacetylmorphine and morphine in cell culture: implications for in vitro studies

Publisher: Elsevier BV

Date: 10-2002

DOI: 10.1016/S0014-2999(02)02365-8

Abstract: Diacetylmorphine deacetylates rapidly to 6-monoacetylmorphine and then to morphine. The immunomodulatory effects of diacetylmorphine are under investigation by several groups utilising various methods including in vitro cell culture however, diacetylmorphine stability under these conditions is unknown. The aim of this study was to quantify diacetylmorphine degradation under cell culture conditions and to determine the mechanism by which this occurs. Diacetylmorphine degradation in a mouse splenocyte mitogenesis assay was investigated. Morphine and 6-monoacetylmorphine were quantified using HPLC with UV detection. After 6 h, approximately 73% of diacetylmorphine had been hydrolysed in the presence of cells. The half-life of diacetylmorphine was 1.4 h in cell media alone and 1.2-2.2 h in incubations containing cells, while the half-life of 6-monoacetylmorphine was 3.1 h in cell media alone and 0.99-1.2 h in incubations containing cells. 6-Monoacetylmorphine and morphine formation were found to be dependent on incubation time and diacetylmorphine concentration, and were not dependent on esterase activity, mitogen concentration, presence of erythrocytes and cell media evaporation. Only morphine formation was dependent on lymphocyte concentration. 6-Monoacetylmorphine formation was independent of cells and appeared to be due to the conditions of the cell culture (pH and temperature), while morphine formation was dependent to a greater extent on cells, but independent of esterase activity. The study highlights the limitations of conclusions made in previous studies which have not recognised diacetylmorphine instability.

Neuroimmunopharmacology at the interface of inflammation and pharmacology relevant to depression

Publisher: Elsevier

Date: 2018

DOI: 10.1016/B978-0-12-811073-7.00012-X

Ventricular tachyarrhythmia during pregnancy in women with heart disease: Data from the ROPAC, a registry from the European Society of Cardiology

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.IJCARD.2016.06.061

Abstract: To describe the incidence, onset, predictors and outcome of ventricular tachyarrhythmia (VTA) in pregnant women with heart disease. VTA during pregnancy will cause maternal morbidity and even mortality and will have impact on fetal outcome. Insufficient data exist on the incidence and outcome of VTA in pregnancy. From January 2007 up to October 2013, 99 hospitals in 39 countries enrolled 2966 pregnancies in women with structural heart disease. Forty-two women (1.4%) developed clinically relevant VTA during pregnancy, which occurred mainly in the third trimester (48%). NYHA class >1 before pregnancy was an independent predictor for VTA. Heart failure during pregnancy was more common in women with VTA than in women without VTA (24% vs. 12%, p=0.03) and maternal mortality was respectively 2.4% and 0.3% (p=0.15). More women with VTA delivered by Cesarean section than women without VTA (68% vs. 47%, p=0.01). Neonatal death, preterm birth (<37weeks), low birthweight (<2500g) and Apgar score <7 occurred more often in women with VTA (4.8% vs. 0.3%, p=0.01 36% vs. 16%, p=0.001 33% vs. 15%, p=0.001 and 25% vs. 7.3%, p=0.001, respectively). VTA occurred in 1.4% of pregnant women with cardiovascular disease, mainly in the third trimester, and was associated with heart failure during pregnancy. NYHA class before pregnancy was predictive. VTA during pregnancy had clear impact on fetal outcome.

Association of Innate Immune Single-Nucleotide Polymorphisms with the Electroencephalogram During Desflurane General Anaesthesia

Publisher: Springer Science and Business Media LLC

Date: 19-12-2013

DOI: 10.1007/S12031-013-0201-7

Abstract: The electroencephalogram (EEG) records the electrical activity of the brain and enables effects of anaesthetic drugs on brain functioning to be monitored. Identification of genes contributing to EEG variability during anaesthesia is important to the clinical application of anaesthesia monitoring and may provide an avenue to identify molecular mechanisms underlying the generation and regulation of brain oscillations. Central immune signalling can impact neuronal activity in the brain and accumulating evidence suggests an important role for cytokines as neuronal modulators. We tested 21 single-nucleotide polymorphisms (SNPs) in immune-related genes for associations with three anaesthesia-induced EEG patterns spindle litude, delta power and alpha power, during general anaesthesia with desflurane in 111 patients undergoing general, gynaecological or orthopaedic surgery. Wide inter-patient variability was observed for all EEG variables. MYD88 rs6853 (p = 6.7 × 10(-4)) and IL-1β rs1143627 in conjunction with rs6853 (p = 1.5 × 10(-3)) were associated with spindle litude, and IL-10 rs1800896 was associated with delta power (p = 1.3 × 10(-2)) suggesting involvement of cytokine signalling in modulation of EEG patterns during desflurane anaesthesia. BDNF rs6265 was associated with alpha power (p = 3.9 × 10(-3)), suggesting differences in neuronal plasticity might also influence EEG patterns during desflurane anaesthesia. This is the first study we are aware of that has investigated genetic polymorphisms that may influence the EEG during general anaesthesia.

Association of IL-1B genetic polymorphisms with an increased risk of opioid and alcohol dependence

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 11-2009

DOI: 10.1097/FPC.0B013E328331E68F

Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement

Publisher: Society for Neuroscience

Date: 15-08-2012

DOI: 10.1523/JNEUROSCI.0684-12.2012

Abstract: Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4 −/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that lifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.

Renal Dysfunction in Patients With Heart Failure With Preserved Versus Reduced Ejection Fraction

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-2012

DOI: 10.1161/CIRCHEARTFAILURE.111.966242

Abstract: Prior studies in heart failure (HF) have used the Modification of Diet in Renal Disease (MDRD) equation to calculate estimated glomerular filtration rate (eGFR). The Chronic Kidney Disease-Epidemiology Collaboration Group (CKD-EPI) equation provides a more-accurate eGFR than the MDRD when compared against the radionuclide gold standard. The prevalence and prognostic import of renal dysfunction in HF if the CKD-EPI equation is used rather than the MDRD is uncertain. We used in idual patient data from 25 prospective studies to stratify patients with HF by eGFR using the CKD-EPI and the MDRD equations and examined survival across eGFR strata. In 20 754 patients (15 962 with HF with reduced ejection fraction [HF-REF] and 4792 with HF with preserved ejection fraction [HF-PEF] mean age, 68 years deaths per 1000 patient-years, 151 95% CI, 146–155), 10 589 (51%) and 11 422 (55%) had an eGFR mL/min using the MDRD and CKD-EPI equations, respectively. Use of the CKD-EPI equation resulted in 3760 (18%) patients being reclassified into different eGFR risk strata 3089 (82%) were placed in a lower eGFR category and exhibited higher all-cause mortality rates (net reclassification improvement with CKD-EPI, 3.7% 95% CI, 1.5%–5.9%). Reduced eGFR was a stronger predictor of all-cause mortality in HF-REF than in HF-PEF. Use of the CKD-EPI rather than the MDRD equation to calculate eGFR leads to higher estimates of renal dysfunction in HF and a more-accurate categorization of mortality risk. Renal function is more closely related to outcomes in HF-REF than in HF-PEF.

Lipopolysaccharide and Morphine-3-Glucuronide-Induced Immune Signalling Increases the Expression of Polysialic Acid in PC12 Cells

Publisher: Springer Science and Business Media LLC

Date: 24-10-2020

DOI: 10.1007/S12035-019-01791-7

Abstract: Polysialic acid (polySia), a long homopolymer of 2,8-linked sialic acids, is abundant in the embryonic brain and is restricted largely in adult brain to regions that exhibit neurogenesis and structural plasticity. In the central nervous system (CNS), polySia is highly important for cell-cell interactions, differentiation, migration and cytokine responses, which are critical neuronal functions regulating intercellular interactions that underlie immune signalling in the CNS. In recent reports, a metabolite of morphine, morphine-3-glucuronide (M3G), has been shown to cause immune signalling in the CNS. In this study, we compared the effects of neurite growth factor (NGF), lipopolysaccharide (LPS) and M3G exposure on the expression of polySia in PC12 cells using immunocytochemistry and Western blot analysis. PolySia was also extracted from stimulated cell proteins by endo-neuraminidase digestion and quantitated using fluorescent labelling followed by HPLC analysis. PolySia expression was significantly increased following NGF, M3G or LPS stimulation when compared with unstimulated cells or cells exposed to the TLR4 antagonist LPS-RS. Additionally, we analyzed the effects of test agent exposure on cell migration and the oxidative stress response of these cells in the presence and absence of polySia expression on their cell surface. We observed an increase in oxidative stress in cells without polySia as well as following M3G or LPS stimulation. Our study provides evidence that polySia expression in neuronal-like PC12 cells is influenced by M3G and LPS exposure alike, suggestive of a role of TLR4 in triggering these events.

Differing prognostic value of pulse pressure in patients with heart failure with reduced or preserved ejection fraction: results from the MAGGIC individual patient meta-analysis

Publisher: Oxford University Press (OUP)

Date: 23-01-2015

DOI: 10.1093/EURHEARTJ/EHU490

Abstract: Low pulse pressure is a marker of adverse outcome in patients with heart failure (HF) and reduced ejection fraction (HF-REF) but the prognostic value of pulse pressure in patients with HF and preserved ejection fraction (HF-PEF) is unknown. We examined the prognostic value of pulse pressure in patients with HF-PEF [ejection fraction (EF) ≥ 50%] and HF-REF. Data from 22 HF studies were examined. Preserved left ventricular ejection fraction (LVEF) was defined as LVEF ≥ 50%. All-cause mortality at 3 years was evaluated in 27 046 patients: 22 038 with HF-REF (4980 deaths) and 5008 with HF-PEF (828 deaths). Pulse pressure was analysed in quintiles in a multivariable model adjusted for the previously reported Meta-Analysis Global Group in Chronic Heart Failure prognostic variables. Heart failure and reduced ejection fraction patients in the lowest pulse pressure quintile had the highest crude and adjusted mortality risk (adjusted hazard ratio 1.68, 95% confidence interval 1.53-1.84) compared with all other pulse pressure groups. For patients with HF-PEF, higher pulse pressure was associated with the highest crude mortality, a gradient that was eliminated after adjustment for other prognostic variables. Lower pulse pressure (especially <53 mmHg) was an independent predictor of mortality in patients with HF-REF, particularly in those with an LVEF < 30% and systolic blood pressure <140 mmHg. Overall, this relationship between pulse pressure and outcome was not consistently observed among patients with HF-PEF.

Relation between weight loss and causes of death in patients with cardiovascular disease: Finding from the SCOUT trial

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2017

DOI: 10.2459/JCM.0000000000000492

CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes

Publisher: Wiley

Date: 03-02-2004

DOI: 10.1046/J.1365-2125.2003.02002.X

Abstract: To determine the Michaelis-Menten kinetics of hydrocodone metabolism to its O- and N-demethylated products, hydromorphone and norhydrocodone, to determine the in idual cytochrome p450 enzymes involved, and to predict the in vivo hepatic intrinsic clearance of hydrocodone via these pathways. Liver microsomes from six CYP2D6 extensive metabolizers (EM) and one CYP2D6 poor metabolizer (PM) were used to determine the kinetics of hydromorphone and norhydrocodone formation. Chemical and antibody inhibitors were used to identify the cytochrome p450 isoforms catalyzing these pathways. Expressed recombinant cytochrome p450 enzymes were used to characterize further the metabolism of hydrocodone. Hydromorphone formation in liver microsomes from CYP2D6 EMs was dependent on a high affinity enzyme (Km = 26 microm) contributing 95%, and to a lesser degree a low affinity enzyme (Km = 3.4 mm). In contrast, only a low affinity enzyme (Km = 8.5 mm) formed this metabolite in the liver from the CYP2D6 PM, with significantly decreased hydromorphone formation compared with the livers from the EMs. Norhydrocodone was formed by a single low affinity enzyme (Km = 5.1 mm) in livers from both CYP2D6 EM and PM. Recombinant CYP2D6 and CYP3A4 formed only hydromorphone and only norhydrocodone, respectively. Hydromorphone formation was inhibited by quinidine (a selective inhibitor of CYP2D6 activity), and monoclonal antibodies specific to CYP2D6. Troleandomycin, ketoconazole (both CYP3A4 inhibitors) and monoclonal antibodies specific for CYP3A4 inhibited norhydrocodone formation. Extrapolation of in vitro to in vivo data resulted in a predicted total hepatic clearance of 227 ml x h-1 x kg-1 and 124 ml x h-1 x kg-1 for CYP2D6 EM and PM, respectively. The O-demethylation of hydrocodone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity cytochrome p450 enzyme. Norhydrocodone formation was attributed to CYP3A4. Comparison of recalculated published clearance data for hydrocodone, with those predicted in the present work, indicate that about 40% of the clearance of hydrocodone is via non-CYP pathways. Our data also suggest that the genetic polymorphisms of CYP2D6 may influence hydrocodone metabolism and its therapeutic efficacy.

Relationship of serum sodium concentration to mortality in a wide spectrum of heart failure patients with preserved and with reduced ejection fraction: an individual patient data meta‐analysis†

Publisher: Wiley

Date: 10-2012

DOI: 10.1093/EURJHF/HFS099

Abstract: Hyponatraemia has been associated with reduced survival in patients with heart failure and reduced ejection fraction (HF-REF). The relationship between serum sodium and outcome is unclear in heart failure with preserved (≥ 50%) ejection fraction (HF-PEF). Therefore, we used a large in idual patient data meta-analysis to study the risk of death associated with hyponatraemia in HF-REF and in HF-PEF. This analysis included 14 766 patients from 22 studies that recruited patients without ejection fraction inclusion criterion at baseline and reported death from any cause. Cox proportional analysis was undertaken for hyponatraemia (sodium <135 mmol/L), adjusted for variables of clinical relevance, and stratified by study. The endpoint was death from any cause at 3 years. Patients with hyponatraemia (n = 1618) and patients with normal serum sodium had similar characteristics as regards to age, gender, and ischaemic aetiology. However, patients with hyponatraemia had higher New York Heart Association class and lower blood pressure. At follow-up, there were 335 deaths among 1618 patients with hyponatraemia (21%) and 2128 deaths among 13 148 patients with normal serum sodium (16%). The risk of death appeared to increase linearly with serum sodium levels <140 mmol/L. Hyponatraemia was identified in 1199 HF-REF patients (11%) and 419 HF-PEF patients (11%). Hyponatraemia was independently predictive of death in both HF-REF [adjusted hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.50-1.91] and HF-PEF (adjusted HR 1.40, 95% CI 1.10-1.79, P for interaction 0.20). Hyponatraemia is a powerful determinant of mortality in patients with HF regardless of ejection fraction. Further work is needed to determine if correction of hyponatraemia translates into clinical benefit.

A Peptide Antagonist of the TLR4–MD2 Interaction

Publisher: Wiley

Date: 24-02-2009

DOI: 10.1002/CBIC.200800769

CYP2B6∗6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: Impact on adverse effects

Publisher: Wiley

Date: 06-2015

DOI: 10.1111/BCP.12614

The Relationship Between Androgens and Days per Month of Period Pain, Pelvic Pain, Headache, and TLR4 Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhoea

Publisher: Informa UK Limited

Date: 03-2021

DOI: 10.2147/JPR.S279253

Select steroid hormone glucuronide metabolites can cause toll-like receptor 4 activation and enhanced pain

Publisher: Elsevier BV

Date: 02-2015

DOI: 10.1016/J.BBI.2014.09.004

Pregnancy in Women With a Mechanical Heart Valve

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 14-07-2015

DOI: 10.1161/CIRCULATIONAHA.115.015242

Abstract: Pregnant women with a mechanical heart valve (MHV) are at a heightened risk of a thrombotic event, and their absolute need for adequate anticoagulation puts them at considerable risk of bleeding and, with some anticoagulants, fetotoxicity. Within the prospective, observational, contemporary, worldwide Registry of Pregnancy and Cardiac disease (ROPAC), we describe the pregnancy outcome of 212 patients with an MHV. We compare them with 134 patients with a tissue heart valve and 2620 other patients without a prosthetic valve. Maternal mortality occurred in 1.4% of the patients with an MHV, in 1.5% of patients with a tissue heart valve ( P =1.000), and in 0.2% of patients without a prosthetic valve ( P =0.025). Mechanical valve thrombosis complicated pregnancy in 10 patients with an MHV (4.7%). In 5 of these patients, the valve thrombosis occurred in the first trimester, and all 5 patients had been switched to some form of heparin. Hemorrhagic events occurred in 23.1% of patients with an MHV, in 5.1% of patients with a tissue heart valve ( P .001), and in 4.9% of patients without a prosthetic valve ( P .001). Only 58% of the patients with an MHV had a pregnancy free of serious adverse events compared with 79% of patients with a tissue heart valve ( P .001) and 78% of patients without a prosthetic valve ( P .001). Vitamin K antagonist use in the first trimester compared with heparin was associated with a higher rate of miscarriage (28.6% versus 9.2% P .001) and late fetal death (7.1% versus 0.7% P =0.016). Women with an MHV have only a 58% chance of experiencing an uncomplicated pregnancy with a live birth. The markedly increased mortality and morbidity warrant extensive prepregnancy counseling and centralization of care.

Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease

Publisher: Informa Healthcare

Date: 25-11-2009

DOI: 10.1517/14656560903426189

Abstract: Ibudilast is a relatively nonselective phosphodiesterase inhibitor which has been marketed for almost 20 years in Japan for treating asthma. More recently it has been found to have anti-inflammatory activity in both the peripheral immune system and in the CNS via glial cell attenuation. This CNS-directed anti-inflammatory activity is of potential use in the treatment of multiple sclerosis, neuropathic pain, and in the improved efficacy and safety of opioids by decreasing opioid tolerance, withdrawal and reinforcement. Its suitable pharmacokinetics and generally good tolerability make it a promising potential treatment for these conditions.

Preventing heart failure: a position paper of the Heart Failure Association in collaboration with the European Association of Preventive Cardiology.

Publisher: Wiley

Date: 2022

DOI: 10.1002/EJHF.2351

Abstract: The heart failure epidemic is growing and its prevention, in order to reduce associated hospital readmission rates and its clinical and economic burden, is a key issue in modern cardiovascular medicine. The present position paper aims to provide practical evidence-based information to support the implementation of effective preventive measures. After reviewing the most common risk factors, an overview of the population attributable risks in different continents is presented, to identify potentially effective opportunities for prevention and to inform preventive strategies. Finally, potential interventions that have been proposed and have been shown to be effective in preventing heart failure are listed.

Air Pollution Distribution Patterns in the San Bernardino Mountains of Southern California: a 40-Year Perspective

Publisher: Hindawi Limited

Date: 2007

DOI: 10.1100/TSW.2007.57

Abstract: Since the mid-1950s, native pines in the San Bernardino Mountains (SBM) in southern California have shown symptoms of decline. Initial studies in 1963 showed that ozone (O 3 ) generated in the upwind Los Angeles Basin was responsible for the injury and decline of sensitive trees. Ambient O 3 decreased significantly by the mid-1990s, resulting in decreased O 3 injury and improved tree growth. Increased growth of trees may also be attributed to elevated atmospheric nitrogen (N) deposition. Since most of the N deposition to mixed conifer forest stands in the SBM results from dry deposition of nitric acid vapor (HNO 3 ) and ammonia (NH 3 ), characterization of spatial and temporal distribution of these two pollutants has become essential. Although maximum daytime O 3 concentrations over last 40 years have significantly decreased (~3-fold), seasonal means have been reduced much less (~1.5-fold), with 2-week long means occasionally exceeding 100 ppb in the western part of the range. In the same area, significantly elevated concentrations of HNO 3 and NH 3 , up to 17.5 and 18.5 μg/m 3 as 2-week averages, respectively, have been determined. Elevated levels of O 3 and increased N deposition together with long-term drought predispose the SBM forests to massive bark beetle attacks making them susceptible to catastrophic fires.

The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials

Publisher: Elsevier BV

Date: 08-2012

DOI: 10.1016/S0140-6736(12)60367-5

Pregnancy outcomes in women with cardiovascular disease: evolving trends over 10 years in the ESC Registry Of Pregnancy And Cardiac disease (ROPAC)

Publisher: Oxford University Press (OUP)

Date: 25-03-2019

DOI: 10.1093/EURHEARTJ/EHZ136

Abstract: Reducing maternal mortality is a World Health Organization (WHO) global health goal. Although maternal deaths due to haemorrhage and infection are declining, those related to heart disease are increasing and are now the most important cause in western countries. The aim is to define contemporary diagnosis-specific outcomes in pregnant women with heart disease. From 2007 to 2018, pregnant women with heart disease were prospectively enrolled in the Registry Of Pregnancy And Cardiac disease (ROPAC). Primary outcome was maternal mortality or heart failure, secondary outcomes were other cardiac, obstetric, and foetal complications. We enrolled 5739 pregnancies the mean age was 29.5. Prevalent diagnoses were congenital (57%) and valvular heart disease (29%). Mortality (overall 0.6%) was highest in the pulmonary arterial hypertension (PAH) group (9%). Heart failure occurred in 11%, arrhythmias in 2%. Delivery was by Caesarean section in 44%. Obstetric and foetal complications occurred in 17% and 21%, respectively. The number of high-risk pregnancies (mWHO Class IV) increased from 0.7% in 2007–2010 to 10.9% in 2015–2018. Determinants for maternal complications were pre-pregnancy heart failure or New York Heart Association & II, systemic ejection fraction & %, mWHO Class 4, and anticoagulants use. After an increase from 2007 to 2009, complication rates fell from 13.2% in 2010 to 9.3% in 2017. Rates of maternal mortality or heart failure were high in women with heart disease. However, from 2010, these rates declined despite the inclusion of more high-risk pregnancies. Highest complication rates occurred in women with PAH.

An optical fibre based ex-vivo device for detection of cytokines

Publisher: Institution of Engineering and Technology

Date: 2017

DOI: 10.1049/CP.2017.0077

Mouse brain glycomics – Insights from exploring the Allen Brain Atlas and the implications for the neuroimmune brain

Publisher: Elsevier BV

Date: 10-2023

DOI: 10.1016/J.BBI.2023.06.024

The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release

Publisher: Elsevier BV

Date: 05-2009

DOI: 10.1016/J.BBI.2009.01.014

An optical fiber based immunosensor for localized detection of IL-1Β in rat spinal cord

Publisher: Elsevier BV

Date: 03-2019

DOI: 10.1016/J.SNB.2018.11.054

Microscopic Modelling of a Wireless Nerve Stimulator Without Electrodes

Publisher: Research Square Platform LLC

Date: 16-05-2022

DOI: 10.21203/RS.3.RS-1657435/V1

Abstract: Electric-field stimulation of neuronal activity can be used to improve the speed of regeneration for severed and damaged nerves. Most techniques, however, require invasive electronic circuitry which can be uncomfortable for the patient and can damage surrounding tissue. A recently suggested technique by Sliow et al instead uses a graft-antenna - a metal ring wrapped around the damaged nerve - powered by an external magnetic stimulation device. This technique requires no electrodes and internal circuitry all power is provided wirelessly. This paper examines the microscopic mechanisms which allow the magnetic stimulation device to cause neural activation via the graft-antenna. A computational model of the system was created and used to find that under magnetic stimulation, erging electric fields appear at the metal ring’s edges. If the magnetic stimulation is sufficient, the gradients of these fields can trigger neural activation in the nerve. In agreement with in vivo measurements on rat sciatic nerves, direct contact between the antenna and the nerve ensures neural activation given sufficient magnetic stimulation. Simulations also showed that the presence of a thin gap between the graft-antenna and the nerve does not preclude neural activation but does reduce its efficacy.

Zerumbone Modulates alpha(2A)-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

Publisher: No publisher found

Date: 2020

DOI: 10.3389/FPHAR.2020.00092

A Nanoparticle-Based Affinity Sensor that Identifies and Selects Highly Cytokine-Secreting Cells

Publisher: Elsevier BV

Date: 10-2019

DOI: 10.1016/J.ISCI.2019.09.019

Chronic Morphine-Induced Changes in Signaling at the A₃Adenosine Receptor Contribute to Morphine-Induced Hyperalgesia, Tolerance, and Withdrawal

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 20-05-2020

DOI: 10.1124/JPET.120.000004

Time course of lipopolysaccharide- and capsaicin-induced cytokine release in an ex vivo mouse model of vaginal inflammation

Publisher: Cold Spring Harbor Laboratory

Date: 12-02-2023

DOI: 10.1101/2023.02.11.528146

Abstract: The neuroimmune interface has been characterised in few areas of the body. The objective of this study was to investigate the neuroimmune interface in the mouse vagina through a novel ex vivo model, to determine whether LPS could directly activate and produce TRPV1-mediated neuronal activation. Concentrations of IL-1β and IL-6 release into the supernatant at different times post ex vivo stimulation with LPS, capsaicin, or a combination of the two were assessed using enzyme-linked immunosorbent assay. There were no differences in the supernatant concentration of IL-6 with different stimulation type nor stimulation time. Supernatant concentrations of IL-1β were greater at the 20 hour time point than the 4 hour time point, and were greater for stimulations involving LPS. There is a clear pattern of pro-inflammatory neuroimmune responses following ex vivo stimulation of mouse vaginal tissues with capsaicin and LPS, evident as an increased IL-1β output. This output is greatest at 20 hours post-stimulation, indicating this neuroimmune response is time-dependent.

University Of Milan

Location: Italy

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University Of Padova

Location: Italy

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Cantù Hospital

Location: Italy

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European Society Of Cardiology

Location: France

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Fondazione Per Il Tuo Cuore Onlus

Location: Italy

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Fondazione RES

Location: Italy

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General Hospital Fatebenefratelli

Location: Italy

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General Hospital G. Fornaroli

Location: Italy

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IRCCS Mario Negri Institute

Location: Italy

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Liceo Classico Berchet

Location: Italy

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University Of Adelaide

Location: Australia

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University Of Colorado At Boulder

Location: United States of America

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Shining Light On The Neuroimmune Interface

Start Date: 2017

End Date: 2020

Funder: United States Air Force

Chronic Pain Following Spinal Cord Injury: The Role Of Immunogenetics And Time Of Injury Pain Treatment

Start Date: 2009

End Date: 2010

Funder: Congressionally Directed Medical Research Programs

Drug Addiction Therapy By Targeting TLR4/MD-2

Start Date: 2019

End Date: 2020

Funder: National Natural Science Foundation of China

Measuring Pain In Livestock: Mechanisms, Objective Biomarkers And Treatments

Start Date: 2018

End Date: 2021

Funder: Australian Research Council

Neural-Glial Interactions And Opioid Abuse: Modulation By Early-Life Experience

Start Date: 2011

End Date: 2015

Funder: National Institutes of Health

Preclinical Development Of TLR Signalling Inhibitors For Prevention Of Preterm Labour And Fetal Inflammatory Injury

Start Date: 2018

End Date: 2020

Funder: National Health and Medical Research Council

Inflammatory Pathways For Novel Therapeutic Interventions In Preterm Delivery

Start Date: 2012

End Date: 2014

Funder: National Health and Medical Research Council

National Live Cell Scanning Platform For Nanoparticle Tracking

Start Date: 2015

End Date: 2015

Funder: Australian Research Council

Volumetric Imaging Facility: Observing The Cell In Its Native Environment

Start Date: 2019

End Date: 2019

Funder: Australian Research Council

Large-volume, Multi-use Micro-computed Tomography

Start Date: 2018

End Date: 2018

Funder: Australian Research Council

ARC Centre Of Excellence For Nanoscale BioPhotonics

Start Date: 2014

End Date: 2020

Funder: Australian Research Council

(Confocal Microscope For High-resolution Microtopographic Analysis Of Surfaces In Historical, Forensic And Polymer Sciences)

Start Date: 2013

End Date: 2013

Funder: Australian Research Council

Priming The Maternal Immune Response To Resist Inflammatory Disorders Of Pregnancy

Start Date: 2016

End Date: 2019

Funder: National Health and Medical Research Council

Linkage Projects - Grant ID: LP160100562

Start Date: 12-2016

End Date: 06-2021

Amount: $340,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP110100297

Start Date: 2011

End Date: 12-2016

Amount: $700,000.00

Funder: Australian Research Council

ARC Future Fellowships - Grant ID: FT180100565

Start Date: 04-2019

End Date: 03-2024

Amount: $998,125.00

Funder: Australian Research Council

ARC Centres Of Excellence - Grant ID: CE140100003

Start Date: 10-2014

End Date: 12-2020

Amount: $23,000,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE190100130

Start Date: 2019

End Date: 12-2019

Amount: $1,480,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE210100155

Start Date: 2021

End Date: 06-2022

Amount: $909,079.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE150100177

Start Date: 2015

End Date: 12-2015

Amount: $440,000.00

Funder: Australian Research Council