BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals.

BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of Bok results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers.

Public health research priorities for WHO on COVID-19 in the South-East Asia Region: results of a prioritization survey.

BACKGROUND: Effectively addressing the coronavirus disease 2019 (COVID-19) pandemic caused by the new pathogen requires continuous generation of evidence to inform decision-making. Despite an unprecedented amount of research occurring globally, the need to identify gaps in knowledge and prioritize a research agenda that is linked to public health action is indisputable. The WHO South-East Asia Region (SEAR) is likely to have region-specific research needs. METHODS: We aimed to identify a priority research agenda for guiding the regional and national response to the COVID-19 pandemic in SEAR countries. An online, anonymous research prioritization exercise using recent WHO guidance was conducted among the technical staff of WHO's country and regional offices engaged with the national COVID-19 response during October 2020. They were each asked to contribute up to five priority research ideas across seven thematic areas. These research ideas were reviewed, consolidated and scored by a core group on six parameters: regional specificity, relevance to the COVID-19 response, feasibility within regional research capacity, time to availability for decision-making, likely impact on practice, and promoting equity and gender responsiveness. The total scores for individual suggestions were organized in descending order, and ideas in the upper tertile were considered to be of high priority. RESULTS: A total of 203 priority research ideas were received from 48 respondents, who were primarily research and emergency response focal points in country and regional offices. These were consolidated into 78 research ideas and scored. The final priority research agenda of 27 items covered all thematic areas-health system (n=10), public health interventions (n=6), disease epidemiology (n=5), socioeconomic and equity (n=3), basic sciences (n=1), clinical sciences (n=1) and pandemic preparedness (n=1). CONCLUSIONS: This exercise, a part of WHO's mandate to "shape the research agenda", can help build a research roadmap ensuring efficient use of limited resources. This prioritized research agenda can act as a catalyst for Member States to accelerate research that could impact the COVID-19 response in SEAR.

Mast cells modulate early responses to Mycobacterium bovis Bacillus Calmette-Guerin by phagocytosis and formation of extracellular traps.

The early interactions between the vaccine Mycobacterium bovis Bacillus Calmette Guerin (BCG) and host peripheral innate immune cells like Mast cells (MCs) may pave the way for generating appropriate protective innate and adaptive immune responses. Mice on administration of BCG by intratracheal instillation showed a massive increase in MC numbers in the infected lung. In vitro co-culture of BCG and rodent Rat Basophilic Leukaemia (RBL-2H3) MCs led to significant killing of BCG. RBL-2H3 MCs were able to phagocytose BCG, take up BCG-derived antigens by macropinocytosis, generate Reactive Oxygen Species (ROS) and degranulate. Further, a few MCs died and released MC extracellular traps (MCETs) having DNA, histones and tryptase to trap BCG. This study highlights the multi-pronged effector responses of MCs on encountering BCG. These responses or their evasion may lead to success or failure of BCG vaccine to provide long term immunity to infections.

A Comparative Study to Evaluate the Efficacy of Curcumin Lozenges (TurmNova®) and Intralesional Corticosteroids with Hyaluronidase in Management of Oral Submucous Fibrosis.

AIM AND OBJECTIVE: This study aims to compare the efficacy of TurmNova® lozenges and its active ingredient "curcumin" as a low-cost, safe, and noninvasive chemopreventive agent with intralesional corticosteroids (with hyaluronidase) in the management of oral submucous fibrosis (OSMF). MATERIALS AND METHODS: A total of 80 patients with group III OSMF (Khanna JN and Andrade NN classification) visiting the dental outpatient clinic of the Department of Oral Medicine and Radiology Rama Dental College Hospital and Research Center, Kanpur, were selected for the study. A total of 80 patients were randomly divided into two groups (40 participants each): group A to whom TurmNova® lozenges containing turmeric extract 100 mg along with clove oil 10 mg three times daily for 3 months were given and group B to whom intralesional infiltration of 2 mL dexamethasone (4 mg/mL) + hyaluronidase 1500 IU dissolved in 0.5 mL of 2% lignocaine twice a week for 3 months was given. Data were analyzed using the IBM SPSS Statistics, version 21 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, version 21.0. Armonk, New York: IBM Corp.) Results: Statistical analysis revealed that there was significant clinical improvement in mouth opening and subjective symptoms, like burning sensation/pain associated with the lesion and tongue protrusion in the group A as compared to group B. CONCLUSION: Curcumin (100 mg) in an innovative delivery system of lozenge results in a higher level of plasma curcumin level. The aforementioned dosages prevent its biotransformation and inactivation by the liver enzymes. Because of these properties, curcumin lozenges are safer, low-cost, and effective alternative treatment in contrast to the present traditional treatment. Further long-term, prospective, large-scale studies need to be done. CLINICAL SIGNIFICANCE: Curcumin has a role in the treatment of oral premalignant conditions and acts as a very effective chemopreventive agent in the prevention of cancer.

Spontaneous Breaking of Lepton Number and the Cosmological Domain Wall Problem.

We show that if global lepton number symmetry is spontaneously broken in a postinflation epoch, then it can lead to the formation of cosmological domain walls. This happens in the well-known "Majoron paradigm" for neutrino mass generation. We propose some realistic examples that allow spontaneous lepton number breaking to be safe from such domain walls.

Trim33 Binds and Silences a Class of Young Endogenous Retroviruses in the Mouse Testis; a Novel Component of the Arms Race between Retrotransposons and the Host Genome.

Transposable elements (TEs) have been active in the mammalian genome for millions of years and the silencing of these elements in the germline is important for the survival of the host. Mice carrying reporter transgenes can be used to model transcriptional silencing. A mutagenesis screen for modifiers of epigenetic gene silencing produced a line with a mutation in Trim33; the mutants displayed increased expression of the reporter transgene. ChIP-seq of Trim33 in testis revealed 9,109 peaks, mostly at promoters. This is the first report of ChIP-seq for Trim33 in any tissue. Comparison with ENCODE datasets showed that regions of high read density for Trim33 had high read density for histone marks associated with transcriptional activity and mapping to TE consensus sequences revealed Trim33 enrichment at RLTR10B, the LTR of one of the youngest retrotransposons in the mouse genome, MMERVK10C. We identified consensus sequences from the 266 regions at which Trim33 ChIP-seq peaks overlapped RLTR10B elements and found a match to the A-Myb DNA-binding site. We found that TRIM33 has E3 ubiquitin ligase activity for A-MYB and regulates its abundance. RNA-seq revealed that mice haploinsufficient for Trim33 had altered expression of a small group of genes in the testis and the gene with the most significant increase was found to be transcribed from an upstream RLTR10B. These studies provide the first evidence that A-Myb has a role in the actions of Trim33 and suggest a role for both A-Myb and Trim33 in the arms race between the transposon and the host. This the first report of any factor specifically regulating RLTR10B and adds to the current literature on the silencing of MMERVK10C retrotransposons. This is also the first report that A-Myb has a role in the transcription of any retrotransposon.

Vitamin D status of adult females residing in Ballabgarh health and demographic surveillance system: A community-based study.

BACKGROUND: Vitamin D deficiency (VDD) is widespread, yet it is the most underdiagnosed and undertreated nutritional deficiency in the world. The prevalence of VDD is estimated to affect over 1 billion people worldwide. OBJECTIVES: The present study was conducted to estimate the prevalence of VDD among adult females aged 20-60 years residing in a rural community of North India, and to find its association with various sociobehavioral risk factors. METHODS: The present study is an analytical cross-sectional study conducted among females aged 20-60 years in rural Ballabgarh. Four hundred women were randomly selected from one of the villages of the Health and Demographic Surveillance System. Semi-structured, pretested interview schedule was administered to the study participants. Fasting venous blood sample was collected for the measurement of plasma sugar level and Vitamin D (25-hydroxyvitamin D). RESULTS: The prevalence of VDD was 90.8% (95% confidence interval [CI] - 87.5-93.3), while that of Vitamin D insufficiency was 8.9% (95% CI - 6.4-12.2). On logistic regression analysis, 24 h calorie intake, protein intake, and prediabetes status of the participants were significantly associated with VDD. CONCLUSION: Very high prevalence of VDD was observed among the females (20-60 years) residing in rural Ballabgarh.

Decadal transition of adult mortality pattern at Ballabgarh HDSS: evidence from verbal autopsy data.

BACKGROUND: Mortality levels and patterns are significant indicators of population health, and are of importance to prioritize the goals of health systems and efficient resource allocation. We ascertained the decadal transition of mortality pattern in adult population aged 15 years and above during the years 2002-2011. METHODS: All adult deaths aged 15 years and above during the years 2002 to 2011 were included in the study. Cause of death was ascertained by verbal autopsy tool for adults which is a validated questionnaire developed at Ballabgarh Health and Demographic Surveillance System (HDSS). Cause and age specific mortality, and mean age at death was determined for individual years. RESULTS: A total of 4,276 deaths (≥15 years) occurred in the Ballabgarh HDSS during the years 2002 to 2011. Of these, 96.8 % deaths were investigated using verbal autopsy tool. Of total deaths investigated, 60.6 % were males. Cardiovascular diseases (19.6 %) were the leading cause of death, followed by respiratory diseases (16.5 %). In the age group of 15-59 years, the most common cause of mortality was external causes of mortality (28.9 %). Most common cause of death was senility (20.8 %) in females, whereas cardiovascular diseases were commonest cause (19.6 %) in males. Road traffic injuries contributed 6.7 % deaths in males compared to 1.5 % in females. Over the years, the proportions of mortality due to cardiovascular diseases had increased (12.6 % to 18.8 %). Mortality proportions had decreased for infectious diseases (12.1 % to 9.5 %) and respiratory diseases (24.7 % to 10.9 %). Mortality due to neoplasms remained nearly stagnant (6.6 % to 6.4 %). Mean age at death due to cardiovascular diseases and neoplasm had increased from 57 years (95 % CI: 52.2-62.9) to 62 years (95 % CI: 59.2-65.4) and 58 years (95 % CI: 53.1-63.2) to 62 years (95 % CI: 57.0-66.7), respectively, during the decade. Mean age at death had decreased for road traffic injuries and infectious diseases from 41 years (95 % CI: 31.7-50.8) to 39 years (95 % CI: 34-43.4) and 53 years (95 % CI: 48.3-58.6) to 50 years (95 % CI: 44.1-55.8), respectively over the years. CONCLUSION: Mortality surveillance using verbal autopsy tool revealed a transition in cause specific deaths from respiratory diseases to cardiovascular diseases over the decade. The apparent epidemiological transition in the community demands reorientation of healthcare priorities.

Induced abortion in villages of Ballabgarh HDSS: rates, trends, causes and determinants.

BACKGROUND: Induced abortion has been legal in India on a broad range of medical and social grounds since 1980s. Often, induced abortion is resorted to as a means for contraception, and has a potential to be misused for sex selective feticide. We assessed the rates, trends, causes and determinants of induced abortions from 2008-12 in a rural community of northern India. METHODS: Present study is a secondary data analysis of pregnancy outcomes at Ballabgarh Health and Demographic Surveillance System from 2008-12. The data was retrieved from the Health and Management Information System maintained at Ballabgarh. Cause of abortion was self-reported by the women who underwent abortion. RESULTS: Of the 11,102 pregnancies, 1,226 (11%) culminated as abortions of which 425 (3.8%) were induced abortions. Spontaneous abortion rate (7.2%) was twice that of induced abortion rate (3.8%). Both abortion rates had an increasing trend during the course of the study period. Self-reported reasons for opting for induced abortions were bleeding per vaginum (23%), unwanted pregnancy (16%), and unviable fetus diagnosed by ultrasonography (11%). Eight percent of the induced abortions were due to the female sex of the fetus. About 11% of the abortions were performed beyond 20 weeks of gestation which was the upper legal permissible gestational age for performing induced abortions in India. About 10% of the abortions were performed by unqualified practitioners. Caste, wealth index, birth order and size of the village population were the factors that were significantly associated with induced abortion. CONCLUSIONS: Though the abortion rate was low, the proportionate contribution of induced abortion was more than what could be expected. Unsafe and sex selective abortion, though illegal, was prevalent. Upper caste and higher socio-economic status families were more likely to opt for induced abortion.

Efficacy of Topical Turmeric, Calendula officinalis, and Tulsi (Ayurvedic Gel) in the Management of Erosive Lichen Planus: A Placebo-Controlled Study.

Background: Chronic mucocutaneous symptoms are a hallmark of lichen planus (LP), an inflammatory disease of the stratified squamous epithelium. The most severe type of mucosal lichen is oral erosive lichen planus (OELP). Materials and Methods: Thirty patients were included in this prospective trial, with fifteen patients each assigned to Group A and Group B. Patients were given a choice between a placebo gel and an ayurvedic gel comprising pure turmeric, Calendula officinalis, and tulsi powder in an oral basis. At each appointment, the patients' reactions to therapy were scored on the Tel Aviv-San Francisco Scale, whereas the degree of the fire was rated using a Visual Analog Scale. Data analysis was carried out using IBM's Statistical Package for the Social Sciences (SPSS) Insights version 21. Results: After receiving ayurvedic gel, patients in Group A reported much less burning than those in Group B (placebo). Group A responded better to therapy overall than Group B. Conclusion: This study's findings support the use of an ayurvedic gel made from pure turmeric, Calendula officinalis, and tulsi powder for the treatment of erosive lichen planus.

Identifying Rab2 Protein as a Key Interactor of Centrin1 Essential for Leishmania donovani Growth.

Previously, we have demonstrated that deletion of a growth-regulating gene (LdCen1) in the Leishmania donovani parasite (LdCen1-/-) attenuated the parasite's intracellular amastigote growth but not the growth of extracellular promastigotes. LdCen1-/- parasites were found to be safe and efficacious against homologous and heterologous Leishmania species as a vaccine candidate in animal models. The reason for the differential growth of LdCen1-/- between the two stages of the parasite needed investigation. Here, we report that LdCen1 interacts with a novel Ras-associated binding protein in L. donovani (LdRab2) to compensate for the growth of LdCen1-/- promastigotes. LdRab2 was isolated by protein pull-down from the parasite lysate, followed by nano-LC-MS/MS identification. The RAB domain sequence and the functional binding partners of the LdRab2 protein were predicted via Search Tool for the Retrieval of Interacting Proteins (STRING) analysis. The closeness of the LdRab2 protein to other reported centrin-binding proteins with different functions in other organisms was analyzed via phylogenetic analysis. Furthermore, in vitro and in silico analyses revealed that LdRab2 also interacts with other L. donovani centrins 3-5. Since centrin is a calcium-binding protein, we further investigated calcium-based interactions and found that the binding of LdRab2 to LdCen1 and LdCen4 is calcium-independent, whereas the interactions with LdCen3 and LdCen5 are calcium-dependent. The colocalization of LdCen1 and LdRab2 at the cellular basal-body region by immunofluorescence supports their possible functional association. The elevated expression of the LdRab2 protein in the mutant promastigotes suggested a probable role in compensating for the promastigote growth of this mutant strain, probably in association with other parasite centrins.

Comparative Analysis of Tissue Copper Levels in Oral Submucous Fibrosis (OSMF) Patients.

Background: Oral submucous fibrosis (OSMF) is a recognized potentially malignant oral condition linked to the consumption of areca nut. Chewing areca nut has been shown to elevate soluble copper levels in mouth fluids. Materials and Methods: Participants: The study included a panel of 30 patients with OSMF from Rama Dental College, Kanpur, India, and 30 nonareca chewing individuals serving as controls. Tissue Sample Collection and Analysis: Buccal mucosal biopsies were obtained from both OSMF patients and controls. The tissue copper concentrations were quantified using mass absorption spectrometry (MAS). Additionally, energy-dispersive X-ray microanalysis (EDX) was employed to identify the presence and distribution of copper in the tissue. Statistical Analysis: Statistical comparisons were performed using appropriate methods, with a P-value of less than 0.05 considered statistically significant. Results: MAS analysis revealed that the mean tissue copper level was 6.2 ± 3.1 micrograms per gram (µg/g) in OSMF specimens (n = 30), slightly higher than the 4.5 ± 2.0 µg/g in the nonareca chewing controls (n = 30) (P = 0.1). EDX analysis showed distinct copper peaks in both the epithelium (22/23) and connective tissue (18/23) of OSMF specimens compared to control biopsies. These findings were corroborated by secondary ion mass spectrometry (SIMS) in a subset of samples. Conclusion: The study revealed higher copper concentrations in buccal mucosal tissue of OSMF patients from Rama Dental College, Kanpur, suggesting a potential connection between copper and the initiation of OSMF.

Role of p53 in cAMP/PKA pathway mediated apoptosis.

Deregulated ß-adrenoceptor/cAMP-PKA pathway is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. We recently had demonstrated that the ß-adrenoceptor/cAMP-PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member BIM in tissues, such as the thymus and the heart. Induction of BIM is driven by the transcriptional co-activator CBP (CREB Binding Protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the BIM promoter site [Lee et al., Cell Death Difference 20(7):941-952 (2013)]. However since CBP is a co-factor for multiple transcription factors, BH-3 only proteins other than Bim could also contribute to this apoptosis pathway. Here we provide evidence for the involvement of p53-CBP axis in apoptosis through Puma/Noxa induction, in response to ß-adrenoceptor activation. Our findings highlight the molecular complexity of pathophysiology associated with a deregulated neuro-endocrine system and for developing novel therapeutic strategies for these diseases.

Iodine deficiency disorders (IDD) control in India.

Iodine deficiency disorders (IDD) constitute the single largest cause of preventable brain damage worldwide. Majority of consequences of IDD are invisible and irreversible but at the same time these are preventable. In India, the entire population is prone to IDD due to deficiency of iodine in the soil of the subcontinent and consequently the food derived from it. To combat the risk of IDD, salt is fortified with iodine. However, an estimated 350 million people do not consume adequately iodized salt and, therefore, are at risk for IDD. Of the 325 districts surveyed in India so far, 263 are IDD-endemic. The current household level iodized salt coverage in India is 91 per cent with 71 per cent households consuming adequately iodized salt. The IDD control goal in India was to reduce the prevalence of IDD below 10 per cent in the entire country by 2012. What is required is a "mission approach" with greater coordination amongst all stakeholders of IDD control efforts in India. Mainstreaming of IDD control in policy making, devising State specific action plans to control IDD, strict implementation of Food Safety and Standards (FSS) Act, 2006, addressing inequities in iodized salt coverage (rural-urban, socio-economic), providing iodized salt in Public Distribution System, strengthening monitoring and evaluation of IDD programme and ensuring sustainability of IDD control activities are essential to achieve sustainable elimination of IDD in India.

Prevalence of dental caries and periodontal diseases, and their association with socio-demographic risk factors among older persons in Delhi, India: a community-based study.

Dental health is often neglected in the older persons, and dental conditions associated with aging are complex, adversely affecting the quality of life. The present study was undertaken to estimate the prevalence of dental caries and periodontal diseases among older persons from Delhi, India, and to study their association with selected socio-behavioral risk factors. We conducted a community-based cross sectional study among persons aged > or = 60 years from Delhi during 2009-2010. A questionnaire was used to interview elderly regarding dental health. The World Health Organization (WHO) oral health assessment form was used for examining the study participants. A total of 448 participants were examined and included in the study. Of the dentate, 47.1% had active dental caries. The mean decayed, missing and filled teeth (DMFT) score for the study population was 14.4. The prevalence of gingival bleeding, periodontal pockets and loss of attachment was 96.6, 89.1, and 80.3%, respectively. The prevalence of tobacco use was 47.9%. Age, frequency of teeth cleaning, and method used for teeth cleaning were statistically associated with the DMFT score. The prevalence of dental caries and periodontal disease was high in the study population, and warrants intervention.

Sustainability analysis of sandstone using smart material by EMI approach.

In India, sandstone was broadly used to construct structures like Agra Fort, Red Fort Delhi, and Allahabad Fort. Around the world, many historical structures were collapsed due to the adverse effect of damages. Structural health monitoring (SHM) is very useful to take appropriate action against the failure of the structure. The electro-mechanical impedance (EMI) technique is used to continuously monitor the damage. A piezoelectric ceramic (PZT) is used in the EMI technique. PZT is a smart material used as a sensor or an actuator in a certain specific manner. The EMI technique work in the 30 to 400 kHz frequency range. This technique helped to analyze the hairline crack, location, and severity of damage to structural elements. A 10 cm length and 5 cm diameter sandstone cylinder was used in the experimental work. An electric marble cutter was used to create the artificial damages of 2 mm, 3 mm, 4 mm, and 5 mm respectively along the length, at the same place in specimens. The conductance signature and susceptance signature were measured for each depth of damage. The comparative result of healthy and damaged state with different depth were concluded based on the conductance signature and susceptance signature form the sample. Statistical methods like root mean square deviation (RMSD) is used for the quantification of damage. The sustainability of sandstone has been analyzed with the help of the EMI technique and RMSD values. This paper motivates the application of the EMI technique to the historical building made of sandstone as key material.

Evaluation of Hearing Performance in Patients with Oral Submucous Fibrosis in Relation to Different Grades.

Background: OSMF is now recognized worldwide as an Indian disease. Blanching and rigidity of the oral mucosa, impaired mobility of the soft palate and tongue, difficulty opening the mouth, burning sensation, lack of gustatory sensation, and mild deafness due to Eustachian tube dysfunction. Soft palatal muscles often affect Eustachian tube function. Materials and Methods: Rama Dental College Hospital and research center Kanpur conducted a cross-sectional study. 60 OSMF patients were randomly selected for this study. Visible light was used for a detailed case history and clinical examination. OSMF was diagnosed by difficulty opening the mouth, blanched oral mucosa, and palpable fibrous bands. Burning, salivation, tongue protrusion, habits, and malignant changes were also diagnostic. ENT specialists used pure tone audiometry to examine the ear (PTA). Results: Out of 60 patients 59 were males and 1 female. The participants who took part in this study ranged in age from 18 to 65. Pure tone audiometry of 120 years, 84 (70%) revealed normal hearing, 10 (8.33%) revealed minimal hearing loss, 14 (11.67%) revealed mild hearing loss and 12 (10%) revealed moderate hearing loss. Conclusion: In order to improve the success rate of treatment, the protocol for managing OSMF patients should therefore include ENT consultation and hearing impairment treatment.

A Study to Assess Anti-Inflammatory Effect of Vitamin D on Gingivitis: A Dose Dependent Randomised Controlled Trial.

Introduction: Vitamin D deficiency increases gingivitis risk. Studies show that higher vitamin D levels reduce inflammation. Materials and Methods: College conducted a double-blind, randomized, controlled trial on 451 people's vitamin D and gingival health at baseline. For three months, participants were given a placebo (group A), 1000 international units (IU) of vitamin D3 per day (group B), 500 IU per day (group C), or 2000 IU per day (group A). Gingival scores were recorded for three months to assess the anti-inflammatory effect (the first, second, and third). Vitamin D levels also affected gingivitis. Results: Vitamin D dose-dependently reduces gingivitis inflammation. Vitamin D administration negatively correlated with gingival index score. Anti-inflammatory vitamin D levels are 32-37 ng/ml. Conclusion: Vitamin D supplementation can reduce gingivitis severity. The optimal blood vitamin D level is 30-35 ng/ml.

Response to antimicrobial resistance in South-East Asia Region.

Antimicrobial resistance (AMR) inflicts significant mortality, morbidity and economic loss in the 11 countries in the WHO South-East Asia Region (SEAR). With technical assistance and advocacy from WHO, all countries have developed their respective National Action Plans on AMR that are aligned with the Global Action Plan. Historically, the WHO Regional Office has been proactive in advocacy at the highest political level. The past decade has seen an enhancement of the country's capacity to combat AMR through national efforts catalyzed and supported through several WHO initiatives at all levels-global, regional and country levels. Several countries including Bangladesh, India, Indonesia, Nepal, Sri Lanka and Thailand have observed a worrying trend of increasing drug resistance, despite heightened awareness and actions. Recent AMR data generated by the countries are indicative of fragmented progress. Lack of technical capacity, financial resources, weak regulatory apparatus, slow behavioural changes at all levels of the antimicrobial stewardship landscape and the COVID-19 pandemic have prevented the effective application of several interventions to minimize the impact of AMR.

Angiogenic remodeling in pediatric EoE is associated with increased levels of VEGF-A, angiogenin, IL-8, and activation of the TNF-α-NFκB pathway.

OBJECTIVES: Eosinophilic esophagitis (EoE) is a clinicopathologic diagnosis characterized by inflammation and infiltration of eosinophils at the esophageal mucosa. The underlying etiology of EoE remains elusive. Inflammatory diseases, such as asthma, are associated with structural remodeling of the airways, which includes angiogenesis. The aims of this study were to determine the angiogenic profile of esophageal mucosa in children presenting with EoE and to evaluate the putative mechanism(s) underlying the early inflammatory angiogenic response observed in EoE. METHODS: Endoscopically obtained biopsy samples from 18 EoE and 18 control pediatric patients were analyzed for angiogenic markers (CD31, von Willebrand factor, vascular cell adhesion molecule-1) and tissue levels of angiogenic factors (vascular endothelial growth factor [VEGF]-A, VEGF-R2, angiogenin and interleukin [IL]-8). Expression levels of angiogenic factors and markers in EoE and control samples were characterized by immunofluorescence analysis and quantitative reverse transcriptase-polymerase chain reaction. Vascular density of biopsy samples was evaluated by immunofluorescence analysis. RESULTS: Samples from patients with EoE exhibited higher levels of von Willebrand factor, CD31, and vascular cell adhesion molecule-1, which is suggestive of neovascularization and an activated endothelium. Moreover, EoE biopsies showed greater levels of the angiogenesis promoters VEGFA, angiogenin, and IL-8. Interestingly, there were greater cellular levels of tumor necrosis factor-α in EoE samples compared with controls. Furthermore, there were higher nuclear levels of p50 and p65 subunits of NFκB and lower cellular levels of the inhibitor of NFκB, IκB-α, in EoE samples compared with controls. CONCLUSIONS: We demonstrate increased angiogenesis in the esophageal mucosa of pediatric patients with EoE. The data also provided evidence that the angiogenic factors VEGF-A, angiogenin, and IL-8 were prominently involved in promoting angiogenic remodeling.