Preconditioning in skeletal muscle

Ischaemia reperfusion injury of skeletal muscle is a major cause of morbidity and mortality in various surgical specialities. Developing a protective method or pharmacological agent that will limit this damage will be of considerable benefit to both patients and doctors. I have used potassium channel openers and calcium as preconditioning agents. The results show that potassium channel openers are a viable option whereas the use of calcium can exacerbate muscle damage. I looked at various protocols of ischaemic and pharmacological preconditioning. The results from both ischaemic and pharmacological preconditioning have shown a comparable decrease with some pharmacological agents in the extent of skeletal muscle infarction both in the early and late period of reperfusion. This decrease in the extent of muscle infarction is associated with changes in the levels of nitric oxide in the circulation. There was preservation of skeletal muscle oxygenation in preconditioned muscle. I have shown that preconditioning of skeletal muscle is a viable option in trying to reduce the amount of damage caused by ischaemia reperfusion injury

High-throughput screening platforms in the discovery of novel drugs for neurodegenerative diseases

© 2021 The Authors. Published by MDPI. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.3390/bioengineering8020030Neurodegenerative diseases (NDDs) are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells in the central nervous system (CNS). Identification of viable therapeutic targets and new treatments for CNS disorders and in particular, for NDDs is a major challenge in the field of drug discovery. These difficulties can be attributed to the diversity of cells involved, extreme complexity of the neural circuits, the limited capacity for tissue regeneration, and our incomplete understanding of the underlying pathological processes. Drug discovery is a complex and multidisciplinary process. The screening attrition rate in current drug discovery protocols mean that only one viable drug may arise from millions of screened compounds resulting in the need to improve discovery technologies and protocols to address the multiple causes of attrition. This has identified the need to screen larger libraries where the use of efficient high-throughput screening (HTS) becomes key in the discovery process. HTS can investigate hun-dreds of thousands of compounds per day. However, if fewer compounds could be screened without compromising the probability of success, the cost and time would be largely reduced. To that end, recent advances in computer-aided design, in silico libraries, and molecular docking software combined with the upscaling of cell-based platforms have evolved to improve screening efficiency with higher predictability and clinical applicability. We review, here, the increasing role of HTS in contemporary drug discovery processes, in particular for NDDs, and evaluate the criteria underlying its successful application. We also discuss the requirement of HTS for novel NDD therapies and examine the major current challenges in validating new drug targets and developing new treatments for NDDs.Published versio

Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type

Objective: To compare intracerebral hemorrhage (ICH) volume and clinical outcome of non–vitamin K oral anticoagulants (NOAC)–associated ICH to warfarin-associated ICH. Methods: In this multicenter cross-sectional observational study of patients with anticoagulant-associated ICH, consecutive patients with NOAC-ICH were compared to those with warfarin-ICH selected from a population of 344 patients with anticoagulant-associated ICH. ICH volume was measured by an observer blinded to clinical details. Outcome measures were ICH volume and clinical outcome adjusted for confounding factors. Results: We compared 11 patients with NOAC-ICH to 52 patients with warfarin-ICH. The median ICH volume was 2.4 mL (interquartile range [IQR] 0.3–5.4 mL) for NOAC-ICH vs 8.9 mL (IQR 4.0–21.3 mL) for warfarin-ICH (p = 0.0028). In univariate linear regression, use of warfarin (difference in cube root volume 1.61; 95% confidence interval [CI] 0.69 to 2.53) and lobar ICH location (compared with nonlobar ICH; difference in cube root volume 1.52; 95% CI 2.20 to 0.85) were associated with larger ICH volumes. In multivariable linear regression adjusting for confounding factors (sex, hypertension, previous ischemic stroke, white matter disease burden, and premorbid modified Rankin Scale score [mRS]), warfarin use remained independently associated with larger ICH (cube root) volumes (coefficient 0.64; 95% CI 0.24 to 1.25; p = 0.042). Ordered logistic regression showed an increased odds of a worse clinical outcome (as measured by discharge mRS) in warfarin-ICH compared with NOAC-ICH: odds ratio 4.46 (95% CI 1.10 to 18.14; p = 0.037). Conclusions: In this small prospective observational study, patients with NOAC-associated ICH had smaller ICH volumes and better clinical outcomes compared with warfarin-associated ICH

Cerebral Small Vessel Disease and Functional Outcome Prediction after Intracerebral Haemorrhage

OBJECTIVE: To determine whether CT-based cerebral small vessel disease (SVD) biomarkers are associated with 6-month functional outcome after intracerebral hemorrhage (ICH), and whether these biomarkers improve the performance of pre-existing ICH score. METHODS: We included 864 patients with acute ICH from a multicentre, hospital-based prospective cohort study. We evaluated CT-based SVD biomarkers (white matter hypodensities [WMH]; lacunes; brain atrophy; and a composite SVD burden score) and their associations with poor 6-month functional outcome (modified Rankin Scale [mRS] score >2). The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow test were used to assess discrimination and calibration of the ICH score with and without SVD biomarkers. RESULTS: In multivariable models (adjusted for ICH score components), WMH presence (OR 1.52, 95%CI 1.12-2.06), cortical atrophy presence (OR 1.80, 95%CI 1.19-2.73), deep atrophy presence (OR 1.66, 95%CI 1.17-2.34), and severe atrophy (either deep or cortical) (OR 1.94, 95%CI 1.36-2.74) were independently associated with poor functional outcome. For the ICH score, the AUROC was 0.71 (95%CI 0.68-0.74). Adding SVD markers did not significantly improve ICH score discrimination; for the best model (adding severe atrophy) the AUROC was 0.73 (95%CI 0.69-0.76). These results were confirmed when considering lobar and non-lobar ICH, separately. CONCLUSIONS: The ICH score has acceptable discrimination for predicting 6-month functional outcome after ICH. CT biomarkers of SVD are associated with functional outcome but adding them does not significantly improve ICH score discrimination

MRI and CT imaging biomarkers of cerebral amyloid angiopathy in lobar intracerebral hemorrhage

BACKGROUND: Cerebral amyloid angiopathy (CAA), a common cause of intracerebral hemorrhage (ICH), is diagnosed using the Boston criteria including magnetic resonance imaging (MRI) biomarkers (cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS). The simplified Edinburgh criteria include computed tomography (CT) biomarkers (subarachnoid extension (SAE) and finger-like projections (FLPs)). The underlying mechanisms and diagnostic accuracy of CT compared to MRI biomarkers of CAA are unknown. METHODS: We included 140 survivors of spontaneous lobar supratentorial ICH with both acute CT and MRI. We assessed associations between MRI and CT biomarkers and the diagnostic accuracy of CT- compared to MRI-based criteria. RESULTS: FLPs were more common in patients with strictly lobar CMB (44.7% vs 23.5%; p = 0.014) and SAE was more common in patients with cSS (61.3% vs 31.2%; p = 0.002). The high probability of the CAA category of the simplified Edinburgh criteria showed 87.2% (95% confidence interval (CI): 78.3-93.4) specificity, 29.6% (95% CI: 18.0-43.6) sensitivity, 59.3% (95% CI: 38.8-77.6) positive predictive value, and 66.4% (95%: CI 56.9-75.0) negative predictive value, 2.3 (95% CI: 1.2-4.6) positive likelihood ratio and 0.8 (95% CI 0.7-1.0) negative likelihood ratio for probable CAA (vs non-probable CAA), defined by the modified Boston criteria; the area under the receiver operating characteristic curve (AUROC) was 0.62 (95% CI: 0.54-0.71). CONCLUSION: In lobar ICH survivors, we found associations between putative biomarkers of parenchymal CAA (FLP and strictly lobar CMBs) and putative biomarkers of leptomeningeal CAA (SAE and cSS). In a hospital population, CT biomarkers might help rule-in probable CAA (diagnosed using the Boston criteria), but their absence is probably not as useful to rule it out, suggesting an important continued role for MRI in ICH survivors with suspected CAA

Association between critical care admission and 6-month functional outcome after spontaneous intracerebral haemorrhage

BACKGROUND: There is uncertainty about the clinical benefit of admission to critical care after spontaneous intracerebral haemorrhage (ICH). PURPOSE: We investigated factors associated with critical care admission after spontaneous ICH and evaluated associations between critical care and 6-month functional outcome. METHODS: We included 825 patients with acute spontaneous non-traumatic ICH, recruited to a prospective multicenter observational study. We evaluated the characteristics associated with critical care admission and poor 6-month functional outcome (modified Rankin Scale, mRS > 3) using univariable (chi-square test and Wilcoxon rank-sum test, as appropriate) and multivariable analysis. RESULTS: 286 patients (38.2%) had poor 6-month functional outcome. Seventy-seven (9.3%) patients were admitted to critical care. Patients admitted to critical care were younger (p < 0.001), had lower GCS score (p < 0.001), larger ICH volume (p < 0.001), more often had intraventricular extension (p = 0.008) and underwent neurosurgery (p < 0.001). Critical care admission was associated with poor functional outcome at 6 months (39/77 [50.7%] vs 286/748 [38.2%]; p = 0.034); adjusted OR 2.43 [95%CI 1.36-4.35], p = 0.003), but not with death (OR 1.29 [95%CI 0.71-2.35; p = 0.4). In ordinal logistic regression, patients admitted to critical care showed an OR 1.47 (95% CI 0.98-2.20; p = 0.07) for a shift in the 6-month modified Rankin Scale. CONCLUSIONS: Admission to critical care is associated with poor 6-month functional outcome after spontaneous ICH but not with death. Patients admitted to critical care were a priori more severely affected. Although adjusted for main known predictors of poor outcome, our findings could still be confounded by unmeasured factors. Establishing the true effectiveness of critical care after ICH requires a randomised trial with clinical outcomes and quality of life assessments

Haptoglobin genotype and outcome after spontaneous intracerebral haemorrhage

OBJECTIVE: Haptoglobin is a haemoglobin-scavenging protein that binds and neutralises free haemoglobin and modulates inflammation and endothelial progenitor cell function. A HP gene copy number variation (CNV) generates HP1 and HP2 alleles, while the single-nucleotide polymorphism rs2000999 influences their levels. The HP1 allele is hypothesised to improve outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH). We investigated the associations of the HP CNV genotype and rs2000999 with haematoma volume, perihaematomal oedema (PHO) volume, functional outcome and mortality after ICH. METHODS: We included patients with neuroimaging-proven ICH, available DNA and 6-month follow-up in an observational cohort study (CROMIS-2). We classified patients into three groups according to the HP CNV: 1-1, 2-1 or 2-2 and also dichotomised HP into HP1-containing genotypes (HP1-1 and HP2-1) and HP2-2 to evaluate the HP1 allele. We measured ICH and PHO volume on CT; PHO was measured by oedema extension distance. Functional outcome was assessed by modified Rankin score (unfavourable outcome defined as mRS 3-6). RESULTS: We included 731 patients (mean age 73.4, 43.5% female). Distribution of HP CNV genotype was: HP1-1 n=132 (18.1%); HP2-1 n=342 (46.8%); and HP2-2 n=257 (35.2%). In the multivariable model mortality comparisons between HP groups, HP2-2 as reference, were as follows: OR HP1-1 0.73, 95% CI 0.34 to 1.56 (p value=0.41) and OR HP2-1 0.5, 95% CI 0.28 to 0.89 (p value=0.02) (overall p value=0.06). We found no evidence of association of HP CNV or rs200999 with functional outcome, ICH volume or PHO volume. CONCLUSION: The HP2-1 genotype might be associated with lower 6-month mortality after ICH; this finding merits further study

Effect of Clay Brick Waste Powder on the Fresh and Hardened Properties of Self-Compacting Concrete: State-of-the-Art and Life Cycle Assessment

Sustainability and reducing environmental damage caused by CO2 emissions have become issues of interest to researchers in the construction sector around the world. Reducing the cement content in concrete by partially substituting it with by-products or waste falls within this field as the cement industry is responsible for 7% of global CO2 emissions. On the other hand, self-compacting concrete (SCC) is one of the special types of concrete that contains a large amount of powder (most of which is cement) to ensure its flow under the influence of its weight without separating its components. Therefore, to produce eco-friendly SCC, many researchers have replaced part of the cement with clay brick waste powder (CBWP) since brick units are among the most widely used building materials after concrete. Accordingly, this study aims to review previous research that included using CBWP in SCC. The effect of these wastes on the fresh, mechanical, durability and microstructural properties of cement was reviewed. Additionally, a comparison between the environmental impacts of SCCs with different CBWP contents has been conducted using the life cycle assessment (LCA) approach. It was found that the highest value of CBWP that can be used without negatively affecting the different properties of concrete is 10% by weight of cement. Moreover, regarding environmental impact, using CBWP as a substitute for cement reduces environmental damage, and the lowest environmental impact that can be achieved per strength unit (MPa) is 37.5%

IL-13 expression by blood T cells and not eosinophils is increased in asthma compared to non-asthmatic eosinophilic bronchitis

<p>Abstract</p> <p>Background</p> <p>In asthma interleukin (IL)-13 is increased in the airway compared with non-asthmatic eosinophilic bronchitis. Whether this differential expression is specific to the airway or is more generalised is uncertain.</p> <p>Methods</p> <p>We sought to examine IL-13 expression in peripheral blood T-cells and eosinophils in asthma and non-asthmatic eosinophilic bronchitis. Peripheral blood CD3+ cell and eosinophil intracellular IL-13 expression from subjects with asthma, non-asthmatic eosinophilic bronchitis and healthy controls was assessed. The effect of priming by asthmatic serum on the release of IL-13 by peripheral blood mononuclear cells from healthy subjects was examined and the serum from these subjects was analysed for a range of chemokines and cytokines.</p> <p>Results</p> <p>The median (IQR)% intracellular IL-13 expression by CD3+ cells was increased in asthma [5.3 (2.7–9.8)%; n = 12] compared to non-asthmatic eosinophilic bronchitis [1.1 (0.5–3)%; n = 7] and healthy controls [1.7 (0.2–3%); n = 9] (p = 0.02), but was not significantly different in eosinophils across the groups. IL-13 released from healthy peripheral blood mononuclear cells (n = 10) was increased by asthmatic serum [117 (47.8–198)pg/ml] compared to control [78.5 (42.6–128)pg/ml; p = 0.02), but was not affected by non-asthmatic serum.</p> <p>Conclusion</p> <p>Our findings support the view that IL-13 expression is increased in peripheral blood-derived T cells in asthma and that asthmatic serum up-regulates IL-13 release from healthy peripheral blood mononuclear cells.</p

Prevalence and demographics of anxiety disorders: a snapshot from a community health centre in Pakistan

<p>Abstract</p> <p>Background</p> <p>The developing world is faced with a high burden of anxiety disorders. The exact prevalence of anxiety disorders in Pakistan is not known. There is a need to develop an evidence base to aid policy development on tackling anxiety and depressive disorders in the country. This is the first pilot study to address the prevalence of anxiety disorders and their association with sociodemographic factors in Pakistan.</p> <p>Methods</p> <p>A cross-sectional study was conducted among people visiting Aga Khan University Hospital (AKUH), a tertiary care facility in Karachi, Pakistan. The point prevalence of anxiety amongst the sample population, which comprised of patients and their attendants, excluding all health care personnel, was assessed using the validated Urdu version of the Hospital Anxiety and Depression Scale (HADS). The questionnaire was administered to 423 people. Descriptive statistics were performed for mean scores and proportions.</p> <p>Results</p> <p>The mean anxiety score of the population was 5.7 ± 3.86. About 28.3% had borderline or pathological anxiety. The factors found to be independently predicted with anxiety were, female sex (odds ratio (OR) = 2.14, 95% CI 1.36–3.36, p = 0.01); physical illness (OR = 1.67, 95% CI 1.06–2.64, p = 0.026); and psychiatric illness (OR = 1.176, 95% CI 1.0–3.1, p = 0.048). In the final multivariate model, female sex (adjusted odds ratio (AOR) = 2, 95% CI 1.28–3.22) and physical illness (AOR = 1.56, 95% CI 0.97–2.48) were found to be significant.</p> <p>Conclusion</p> <p>Further studies via nationally representative surveys need to be undertaken to fully grasp the scope of this emerging public health issue in Pakistan.</p