Novel vascular endothelial growth factor blocker improves cellular viability and reduces hypobaric hypoxia‐induced vascular leakage and oedema in rat brain

Vascular endothelial growth factor (VEGF) is an important cerebral angiogenic and permeability factor under hypoxia. There is a need to find effective molecules that may ameliorate hypoxia‐induced cerebral oedema. In silico identification of novel candidate molecules that block VEGF‐A site were identified and validated with a Ramachandran plot. The active site residues of VEGF‐A were detected by Pocketfinder, CASTp, and DogSiteScorer. Based on in silico data, three VEGF‐A blocker (VAB) candidate molecules (VAB1, VAB2, and VAB3) were checked for improvement in cellular viability and regulation of VEGF levels in N2a cells under hypoxia (0.5% O₂). Additionally, the best candidate molecule's efficacy was assessed in male Sprague‐Dawley rats for its ameliorative effect on cerebral oedema and vascular leakage under hypobaric hypoxia 7260 m. All experimental results were compared with the commercially available VEGF blocker sunitinib. Vascular endothelial growth factor‐A blocker 1 was found most effective in increasing cellular viability and maintaining normal VEGF levels under hypoxia (0.5% oxygen) in N2a cells. Vascular endothelial growth factor‐A blocker 1 effectively restored VEGF levels, decreased cerebral oedema, and reduced vascular leakage under hypobaric hypoxia when compared to sunitinib‐treated rats. Vascular endothelial growth factor‐A blocker 1 may be a promising candidate molecule for ameliorating hypobaric hypoxia‐induced vasogenic oedema by regulating VEGF levels.     

Analysis of misoprostol and chlorhexidine policy gains in Pakistan: the advocacy experience of Mercy Corps Pakistan

While Pakistan has made progress toward achieving Millennium Development Goal 5 for maternal health, it is unlikely to achieve the target; further, it is also not on track for Millennium Development Goal 4 regarding child health. Two low-cost, temperature stable and life-saving drugs, misoprostol and chlorhexidine, can respectively avert maternal and newborn deaths, and are particularly pertinent for poor and marginalized areas which bear the brunt of maternal and newborn deaths in Pakistan. In response, Mercy Corps led focused advocacy efforts to promote changes in policies, protocols, and regulatory environments for misoprostol (2012–2014) and for chlorhexidine (2014). These short-duration advocacy projects facilitated significant policy gains, such as inclusion of misoprostol and chlorhexidine into province-specific essential drug lists, development and endorsement of clinical protocols for the two drugs by provincial health departments, inclusion of misoprostol into pre-service training curriculum for several health cadres, and application for registration of chlorhexidine (at the concentration required for newborn care) by two pharmaceutical companies. These results were achieved by a consultative and evidence-based process which generated feedback from community members, program implementers, and policymakers, and ultimately put the government in the driver’s seat to facilitate change. Community Action Dialogue forums were linked with provincial-level Technical Working Groups and Provincial Steering Committees, who passed on endorsed recommendations to the Health Secretary. The key factors which facilitated change were the identification of champions within the provincial health departments, prioritization of relationship building and follow-up, focus on concrete advocacy aims rather than broad objectives, and the use of multi-stakeholder forums to secure an enabling environment for the policy changes to take root. While these advocacy initiatives resulted in significant policy changes in Pakistan’s devolved health system, to ensure these policy changes have an impact on health outcomes, Pakistan should focus on the scale-up of appropriate use of chlorhexidine and misoprostol. Further, future policy initiatives in Pakistan should make use of similar multi-stakeholder policy forums, while ensuring a third party to facilitate the process so that civil society and community voices are not lost in the policy development discussion.     

Effects of melatonin supplementation on disease activity,oxidative stress,inflammatory, and metabolic parameters in patients with rheumatoid arthritis: a randomized double-blind placebo-controlled trial

Clinical Rheumatology - Considering the pathologic significance of inflammation and oxidative stress in rheumatoid arthritis (RA) as well as the antioxidant, anti-inflammatory and hypolipidemic...     

Novel Z Scores to Correct Biases Due to Ventricular Volume Indexing to Body Surface Area in Adolescents and Young Adults

BackgroundReference values for cardiac magnetic resonance imaging (cMRI) in children and young adults are scarce. This leads to risk stratification of patients with congenital heart diseases being based on volumes indexed to body surface area (BSA). We aimed to produce cMRI Z score equations for ventricular volumes in children and young adults and to test whether indexing to BSA resulted in an incorrect assessment of ventricular dilation according to sex, body composition, and growth.MethodsWe retrospectively included 372 subjects aged < 26 years with either normal hearts or conditions with no impact on ventricular volumes (reference group), and 205 subjects with repaired tetralogy of Fallot (TOF) aged < 26 years. We generated Z score equations by means of multivariable regression modelling. Right ventricular dilation was assessed with the use of Z scores and compared with indexing to BSA in TOF subjects.ResultsVentricular volume Z scores were independent from age, sex, and anthropometric measurements, although volumes indexed to BSA showed significant residual association with sex and body size. In TOF subjects, indexing overestimated dilation in growing children and underestimated dilation in female compared with male subjects, and in overweight compared with lean subjects.ConclusionsIndexed ventricular volumes measured with cMRI did not completely adjust for body size and resulted in a differential error in the assessment of ventricular dilation according to sex and body size. Our proposed Z score equations solved this problem. Future studies should evaluate if ventricular volumes expressed as Z scores have a better prognostic value than volumes indexed to BSA.     

Efficacy of tight control strategy in the treatment of adult-onset Still disease

Clinical Rheumatology - Adult-onset Still’s disease (AOSD) characterized by a high spiking fever, skin rash, arthritis, and leukocytosis. The aim of the present study was considering the...     

Prognostic Impact of Serum Growth Differentiation Factor 15 Level in Acute Myeloid Leukemia Patients

Growth differentiation factor 15 (GDF15) plays an important role in cancer pathophysiology and prognosis. However, limited studies analyzed its level and prognostic value in acute myeloid leukemia (AML) patients. This study included 56 adult AML patients. Serum GDF15 level was measured at diagnosis in all patients by enzyme-linked immunosorbent assay. Remission and survival statuses were assessed at 90 days following treatment. GDF15 level was significantly higher in patients than in controls (P < 0.001). GDF15 level correlated positively with age (P < 0.001), hemoglobin level (P = 0.027), and platelet count (P = 0.024). High GDF15 above the median level was associated with inferior OS (P = 0.044) together with high platelet count (P = 0.006) and high bone marrow blast percent (P = 0.038). There was no statistically significant difference between patients with GDF15 above and below the median level regarding DFS (P = 0.881). On multivariate analysis for OS, GDF15 level was an independent risk factor (P = 0.047). In conclusion, serum GDF15 level is significantly elevated in AML patients and high GDF15 level is associated with inferior OS.     

Molecular basis of non-alcoholic fatty liver disease and metabolic syndrome in a subset of South Asians

International Journal of Diabetes in Developing Countries - Metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) are emerging threats in Pakistan. The prevalence of MetS is...     

Paediatric gastrointestinal disorders in SARS-CoV-2 infection: Epidemiological and clinical implications

The coronavirus disease 2019 (COVID-19) pandemic is a threat worldwide for individuals of all ages, including children. Gastrointestinal manifestations could be the initial presenting manifestation in many patients, especially in children. These symptoms are more common in patients with severe disease than in patients with non-severe disease. Approximately 48.1% of patients had a stool sample that was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA. Children typically form 1%-8% of all laboratory-confirmed cases of SARS-CoV-2. Gastrointestinal manifestations of COVID-19 in children are not rare, with a prevalence between 0 and 88%, and a wide variety of presentations, including diarrhoea, vomiting, and abdominal pain, can develop before, with or after the development of respiratory symptoms. Atypical manifestations such as appendicitis or liver injury could also appear, especially in the presence of multisystem inflammatory disease. In this review, we discussed the epidemiology of COVID-19 gastrointestinal diseases in children as well as their implications on the diagnosis, misdiagnosis, prognosis, and faecal-oral transmission route of COVID-19 and the impact of gastrointestinal diseases on the gut microbiome, child nutrition, and disease management.     

The association of childhood asthma with mental health and developmental comorbidities in low-income families

Objective: The objective of the study was to determine the relationship of childhood asthma with mental health and developmental indicators in low-income families. Methods: Parents/guardians of approximately 400 children, aged 2–14 years, were recruited from a charity hospital serving low income neighborhoods in the outskirts of Karachi, Pakistan. Mothers of children were interviewed in their local language by a trained nurse. Eight self-reported comorbidities were grouped into two constructs based on factor analysis and conveniently labeled as mental health (anxiety, attention and behavioral problems) and developmental problems (learning, developmental delay, hearing impairment, sleep and speech problems). Data were analyzed using multiple logistic regression, adjusted for age, sex, presence of older siblings, number of people in the household, child birth weight, presence of mold, and family history of asthma or hay fever. Results: Children with asthma had 18 times greater odds of mental health problems (adjusted OR?=?18.0, 95% CI: 9.2, 35.1) as compared to children without asthma. The odds of developmental problems were more than 14 times greater for children with asthma (adjusted OR?=?14.3, 95% CI: 7.8, 26.1) as compared to children without asthma. Conclusions: This study found mental and developmental adverse consequences of childhood asthma in low-income families. Identifying and treating asthma at an early age could reduce the burden of comorbidities in this population.