Neutral or detrimental effects of TREM2 agonist antibodies in preclinical models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's Disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.Significance Statement Multiple TREM2 agonist antibodies are investigated in mouse models of Alzheimer's Disease and Multiple Sclerosis. Despite agonism in culture models and after acute dosing in mice, antibodies do not show benefit in overall AD pathology and worsen recovery after demyelination.

Early and mid-term outcomes of double-chambered right ventricle repair: An 8-year experience.

BACKGROUND/AIM: Double-chambered right ventricle is a rare and progressive condition that is characterised by obstruction of the right ventricular tract. Double-chambered right ventricle is usually associated with ventricular septal defect. Early surgical intervention is recommended in patients with these defects. Based on this background, the present study aimed to review early and midterm outcomes of primary repair after double-chambered right ventricle. METHODS: Between January 2014 and June 2021, 64 patients with a mean age of 13.42 ± 12.31 years underwent surgical repair for double-chambered right ventricle. The clinical outcomes of these patients were reviewed and assessed retrospectively. RESULTS: An associated ventricular septal defect was present in all the recruited patients; 48 (75%) patients of sub-arterial type, 15 (23.4%) of perimembranous, and 1 (1.6%) patient of muscular type. The patients were followed up for a mean period of 46.73 ± 27.37 months. During their follow-up, a significant decrease in the mean pressure gradient from 62.33 ± 5.52 mmHg preoperatively to 15.73 ± 2.94 mmHg postoperatively was observed (p < 0.001). Notably, there were no hospital deaths. CONCLUSIONS: The development of double-chambered right ventricle in association with ventricular septal defect results in an increased pressure gradient within the right ventricle. The defect needs correction in a timely manner. In our experience, the surgical correction of double-chambered right ventricle is safe and shows excellent early and mid-term results.

A Study of Prevalence of Renal Function Abnormalities and Their Association with the Individual Components of Metabolic Syndrome.

INTRODUCTION: Metabolic syndrome (MetS) is one of the most important emerging pandemics of the 21st century and is associated with renal dysfunction in a significant number of subjects, the association of which is shown to be of greater significance in the South Asian population. AIMS AND OBJECTIVES: The prevalence of renal dysfunction in patients with MetS is the primary outcome. The secondary outcome is to assess the strength and significance of the association between the individual components of MetS and the presence of renal dysfunction. MATERIALS AND METHODS: This is a hospital-based cross-sectional observational study conducted for 2 years in a tertiary care hospital in India. A total of 100 diagnosed subjects of MetS were taken as cases and underwent relevant blood tests. Data were collected and analyzed in a Statistical Package for the Social Sciences (SPSS) v29 sheet. RESULTS: Over a period of 18 months, 100 subjects with MetS were documented, among which 66% had albuminuria, with microalbuminuria being 24% and the rest being macroalbuminuria. Among the same subjects, 30% had an estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73m2. Waist circumference (WC) [measured by the National Institutes of Health (NIH) protocol] had the strongest association with increased albuminuria (r = 0.540; p-value < 0.001) as well as reduced eGFR (r = 0.460; p-value < 0.001). CONCLUSION: All the components of MetS, for example, increased WC, hypertension, increased fasting glucose, raised triglyceride (TG), and low high-density lipoprotein (HDL), have statistically significant correlations with increased urine albumin-to-creatinine ratio (ACR) and decreased eGFR, signifying glomerular injury and renal dysfunction, respectively.

Tracking Missing Deaths: An Exploratory Study on the Mortality Impact of COVID-19 in Kozhikode City, India.

BACKGROUND: The debate over the extent of the mortality impact of COVID-19 in India is still unsettled. OBJECTIVES: This article contributes to the debate, seeking to explore the true mortality impact of the pandemic, by answering four interrelated questions. First, is there any discrepancy between recorded and actual death count? Second, if so, how large it is? Third, what is the extent of misclassification of COVID-19 mortality, and fourth, what is the magnitude of deaths that could be indirectly linked to COVID-19? MATERIALS AND METHODS: To answer the questions, we explored three sources of data-all-cause mortality data from the civil registration system, records maintained at the burial grounds/cemeteries and crematoriums, and a household survey. The data collection period was between August 2021 and November 2021. The instrument used for data collection of verbal autopsies was built on the instrument proposed by the World Health Organization for adult mortality. RESULTS: The results revealed that deaths due to various causes including COVID-19 increased considerably at some points in 2020-2021 compared to the base year 2019 in the study setting. Notably, 5.5% of the noninstitutional deaths were unreported at the time of the survey and many deaths were plausibly misclassified, leading to undercounting of COVID-19 deaths. Overall, about half of our sampled deaths (48%) had either direct or indirect attribution to the pandemic. CONCLUSION: The extent of undercounting of pandemic-related deaths is likely to be either similar or worse in other states. To get reliable state and national estimates, policymakers should conduct a large-scale study.

Reducing infant and child mortality: assessing the social inclusiveness of child health care policies and programmes in three states of India.

BACKGROUND: Even though the overall infant mortality rate and child mortality rate have considerably declined in India, the marginalised groups-Scheduled Caste, and Scheduled Tribe, continue to have higher mortality rates. This study looks at the changes in IMR and CMR amongst disadvantaged and advanced social groups at the national level and in three states of India. DATA AND METHODS: Data from five rounds of National Family Health Survey spanning nearly three decades have been used to measure IMR and CMR according to the social groups for India and for selected states-Bihar, West Bengal, and Tamil Nadu. The relative hazard curves were drawn to understand which social group's children face a higher risk of dying in the first year of birth and between first year and age four in those three states. Further, a log-rank test was applied to examine whether the differences between the survival curves or distributions of the three social groups are statistically significant. Finally, the binary logit regression model was applied to investigate the effect of ethnicity, and other socio-economic and demographic covariates on the risk of infant and child deaths (1-4 years) in the country and in selected states. RESULTS: Hazard curve shows the probability of death within one year of birth was highest among the children belonging to the ST families, followed by SCs in India. And, the CMR was found to be higher amongst the STs compared to all other social groups as well at the national level. While Bihar had a remarkably high infant and child mortality rates, Tamil Nadu possessed the lowest child death rates irrespective of class, caste, and religion. The regression model revealed that most of the caste/tribe gaps in infant and child deaths might be attributed to the place of residence, mother's level of education, economic status, and the number of children in a family. Notably, the multivariate analysis showed that ethnicity was an independent risk factor, when controlled for socioeconomic status. CONCLUSION: The study detects the persistence of significant caste/tribe differentials in infant and child mortality in India. Poverty, education and health care access issues could be the possible reasons for the premature deaths of the children from deprived castes and tribes. There is a need to critically analyse the current health programmes aimed at reducing IMR and CMR to make them attuned to the needs of the marginalised communities.

Surgical outcomes of double-orifice mitral valve repair in patients with atrioventricular canal defects: a systematic review and meta-analysis.

INTRODUCTION: Double-orifice mitral valve or left atrioventricular valve is a rare congenital cardiac anomaly that may be associated with an atrioventricular septal defect. The surgical management of double-orifice mitral valve/double-orifice left atrioventricular valve with atrioventricular septal defect is highly challenging with acceptable clinical outcomes. This meta-analysis is aimed to evaluate the surgical outcomes of double-orifice mitral valve/double-orifice left atrioventricular valve repair in patients with atrioventricular septal defect. METHODS AND RESULTS: A total of eight studies were retrieved from the literature by searching through PubMed, Google Scholar, Embase, and Cochrane databases. Using Bayesian hierarchical models, we estimated the pooled proportion of incidence of double-orifice mitral valve/double-orifice left atrioventricular valve with atrioventricular septal defect as 4.88% in patients who underwent surgical repair (7 studies; 3295 patients; 95% credible interval [CI] 4.2-5.7%). As compared to pre-operative regurgitation, the pooled proportions of post-operative regurgitation were significantly low in patients with moderate status: 5.1 versus 26.39% and severe status: 5.7 versus 29.38% [8 studies; 171 patients]. Moreover, the heterogeneity test revealed consistency in the data (p < 0.05). Lastly, the pooled estimated proportions of early and late mortality following surgical interventions were low, that is, 5 and 7.4%, respectively. CONCLUSION: The surgical management of moderate to severe regurgitation showed corrective benefits post-operatively and was associated with low incidence of early mortality and re-operation.

Satellite Epidemic of Covid-19 Associated Mucormycosis in India: A Multi-Site Observational Study.

BACKGROUND: Sudden upsurge in cases of COVID-19 Associated Mucormycosis (CAM) following the second wave of the COVID-19 pandemic was recorded in India. This study describes the clinical characteristics, management and outcomes of CAM cases, and factors associated with mortality. METHODS: Microbiologically confirmed CAM cases were enrolled from April 2021 to September 2021 from ten diverse geographical locations in India. Data were collected using a structured questionnaire and entered into a web portal designed specifically for this investigation. Bivariate analyses and logistic regression were conducted using R version 4.0.2. RESULTS: A total of 336 CAM patients were enrolled; the majority were male (n = 232, 69.1%), literate (n = 261, 77.7%), and employed (n = 224, 66.7%). The commonest presenting symptoms in our cohort of patients were oro-facial and ophthalmological in nature. The median (Interquartile Range; IQR) interval between COVID diagnosis and admission due to mucormycosis was 31 (18, 47) days, whereas the median duration of symptoms of CAM before hospitalization was 10 (5, 20) days. All CAM cases received antifungal treatment, and debridement (either surgical or endoscopic or both) was carried out in the majority of them (326, 97.02%). Twenty-three (6.9%) of the enrolled CAM cases expired. The odds of death in CAM patients increased with an increase in HbA1c level (aOR: 1.34, 95%CI: 1.05, 1.72) following adjustment for age, gender, education and employment status. CONCLUSION: A longer vigil of around 4-6 weeks post-COVID-19 diagnosis is suggested for earlier diagnosis of CAM. Better glycemic control may avert mortality in admitted CAM cases.

A case control investigation of COVID-19 associated mucormycosis in India.

BACKGROUND: Increased occurrence of mucormycosis during the second wave of COVID-19 pandemic in early 2021 in India prompted us to undertake a multi-site case-control investigation. The objectives were to examine the monthly trend of COVID-19 Associated Mucormycosis (CAM) cases among in-patients and to identify factors associated with development of CAM. METHODS: Eleven study sites were involved across India; archived records since 1st January 2021 till 30th September 2021 were used for trend analysis. The cases and controls were enrolled during 15th June 2021 to 30th September 2021. Data were collected using a semi-structured questionnaire. Among 1211 enrolled participants, 336 were CAM cases and 875 were COVID-19 positive non-mucormycosis controls. RESULTS: CAM-case admissions reached their peak in May 2021 like a satellite epidemic after a month of in-patient admission peak recorded due to COVID-19. The odds of developing CAM increased with the history of working in a dusty environment (adjusted odds ratio; aOR 3.24, 95% CI 1.34, 7.82), diabetes mellitus (aOR: 31.83, 95% CI 13.96, 72.63), longer duration of hospital stay (aOR: 1.06, 95% CI 1.02, 1.11) and use of methylprednisolone (aOR: 2.71, 95% CI 1.37, 5.37) following adjustment for age, gender, occupation, education, type of houses used for living, requirement of ventilatory support and route of steroid administration. Higher proportion of CAM cases required supplemental oxygen compared to the controls; use of non-rebreather mask (NRBM) was associated as a protective factor against mucormycosis compared to face masks (aOR: 0.18, 95% CI 0.08, 0.41). Genomic sequencing of archived respiratory samples revealed similar occurrences of Delta and Delta derivates of SARS-CoV-2 infection in both cases and controls. CONCLUSIONS: Appropriate management of hyperglycemia, judicious use of steroids and use of NRBM during oxygen supplementation among COVID-19 patients have the potential to reduce the risk of occurrence of mucormycosis. Avoiding exposure to dusty environment would add to such prevention efforts.

Improving access to medicines by popularising generics: a study of 'India's People's Medicine' scheme in two districts of Maharashtra.

BACKGROUND: In spite of being the 'pharmacy of the world', access to essential medicines for a large majority of Indians is constrained by both physical and financial reasons. According to an estimate, medicines account for 69% of household out-of-pocket spending on health care. To make quality generic medicine affordable, India's People's Medicine Scheme (Jan Aushadhi) was launched in 2008 and then revamped and rebranded as Pradhan Mantri Bhartiya Jan Ausadhi Pariyojana (PMBJP) in 2015. The current study focuses on the availability, affordability and acceptability aspects of PMBJP essential medicines. METHODS: We have used a mixed-methods approach, with the survey-based quantitative component supplemented by a qualitative component consisting of in-depth interviews (IDIs). The survey was conducted in 11 PMBJP pharmacies in Mumbai and Palghar. Data were gathered on the availability, stock-outs, price and affordability of 35 essential medicines and 2 consumables. RESULTS: Apart from the limited coverage of essential medicines and the significant presence of Fixed dose combinations (FDCs) in the PMBJP medicine list, the availability of surveyed essential drugs was also found to be low (47%) in PMBJP outlets. Across Mumbai and Palghar districts, around 50% and 42% of medicines were found to be out of stock for the period of 3-6 months respectively. The cost of generic medicines of PMBJP outlets for treating various conditions range from 0.01 days' wages to 0.47 days' wages for the lowest paid unskilled worker in Maharashtra. CONCLUSIONS: The study findings show that PMBJP's unbranded generics offer great opportunities for substantial cost savings. But, in order to fully realise the potential of this scheme, some policy actions are urgently required. First, the PMBJP drug list must include all essential drugs that feature in NLEM. Second, BPPI should procure only those drugs that pass the bioequivalence test. Third, compulsory de-branding of generics should be done in a phased manner. Fourth, PMBJP's medicine procurement and distribution policies must be reviewed to address the supply chain issues. Moreover, there is a need for major pharmaceutical policy reforms to promote generic medicines in a big way. Regulations to support mandatory generic prescribing and generic substitution by pharmacists are needed.

Successful endovascular repair with coil embolization of ruptured right internal thoracic artery aneurysm.

Internal thoracic artery aneurysms (ITAAs) are rare with wide variation in clinical presentation and a high risk of rupture. Endovascular techniques are increasingly being used for treatment of such aneurysms over surgical repair in recent times. A 34-year-old male presented with progressive swelling of the right anterior chest wall for 2 weeks and was diagnosed with right internal thoracic artery aneurysm with contained rupture. He underwent successful endovascular repair with coil embolization of ruptured right ITAA. Post intervention computed tomography (CT) angiography confirmed sealing of the ruptured aneurysm with no residual filling of the sac. At six months follow-up he is doing well with complete resolution of hematoma. This case demonstrates that an endovascular approach with coil embolization is a feasible and safe option for treating the rare ruptured ITAAs.

Os aneurismas da artéria torácica interna (ITAAs) são raros, com ampla variação na apresentação clínica e alto risco de ruptura. As técnicas endovasculares têm sido cada vez mais utilizadas para o tratamento desses aneurismas em relação ao reparo cirúrgico. Um homem de 34 anos de idade apresentou edema progressivo da parede torácica anterior direita por 2 semanas e foi diagnosticado com aneurisma da artéria mamária interna direita com ruptura contida. Ele foi submetido a reparo endovascular bem-sucedido, com embolização de ITAA direito roto. A angiotomografia computadorizada (angioTC) pós-intervenção confirmou o selamento do aneurisma rompido, sem enchimento residual do saco. No seguimento de 6 meses, ele estava bem, com resolução completa do hematoma. Este caso demonstra que a abordagem endovascular com embolização com molas é uma opção viável e segura no tratamento dos raros ITAAs rotos.

A rare case of lung abscess due to esophageo-pulmonary fistula in asymptomatic carcinoma of esophagus.

Acquired esophago-respiratory fistulae are usually esophago-tracheal or esophago-bronchial. Esophago-pulmonary fistulae are rare. Most patients present with cardinal symptoms of esophageal carcinoma or esophago-pulmonary fistula leading to early diagnosis. We report a 56-year-old female with an unusual presentation. She presented with high grade fever with chills and rigor, cough with mucopurulent expectoration and shortness of breath for 15 days without dysphagia, nausea, vomiting or chest pain. Clinically and radiologically a diagnosis of lung abscess was entertained and she was treated with multiple antibiotics without any improvement. Contrast Enhanced Computed Tomography (CECT) chest revealed esophageal malignancy with esophageal-pulmonary fistula communicating with abscess cavity. Patient responded to palliation with self-expandable esophageal stent and drainage of abscess. Although rare, asymptomatic malignant esophageal disease should be considered in the differential diagnosis of lung abscess, which does not follow a usual course. Keywords: Lung abscess, Esophageal cancer, Esophageo-pulmonary fistula, Self expandable metallic stent.

COVID Associated Mucormycosis: A Study on the Spectrum of Clinical, Biochemical and Radiological Findings in A Series of Ten Patients.

BACKGROUND: There is more than twofold rise in prevalence of mucormycosis cases in India during the COVID-19 pandemic which needs to be evaluated. AIMS: The study aimed to document the spectrum of cases of mucormycosis seen at our Institute during COVID-19 times. METHODS: The study is a retrospective observational study carried out at our Institute from May 2021 to mid-June 2021. All patients with biopsy-proven mucormycosis were enrolled in the study. The patients were subjected to complete history taking, ophthalmological examination, and imaging studies. The patients were treated with a multidisciplinary approach with antifungal therapy as well as surgical intervention when needed. RESULTS: Ten patients (n=10) were seen, with a mean age of 50.3 years. The major risk factors included recent use of steroids, uncontrolled diabetes, and CKD. The most common presentation was swelling of unilateral eye and ptosis, followed by loss of vision. Inflammatory marker (CRP) and d-dimer were raised at presentation in all cases. Imaging showed the spread of infection from paranasal sinus to orbit and brain via cavernous sinus, which was a poor prognostic factor. Intravenous Amphotericin-B was given to all patients for at least 4 weeks. Two patients were discharged after completion of treatment and mortality was seen in three patients. CONCLUSION: We present an array of COVID-associated-mucormycosis (CAM) cases from Eastern India. CAM is presenting with rhino-orbito-cerebral involvement. There is poor outcome with cerebral involvement and high incidence of adverse effects with deoxycholate formulation of amphotericin-B. The causal association of COVID-19 with mucormycosis needs to be unearthed but possible preventive role of anticoagulation should be evaluated.

Physical and functional interaction between nucleoid-associated proteins HU and Lsr2 of Mycobacterium tuberculosis: altered DNA binding and gene regulation.

Nucleoid-associated proteins (NAPs) in bacteria contribute to key activities such as DNA compaction, chromosome organization and regulation of gene expression. HU and Lsr2 are two principal NAPs in Mycobacterium tuberculosis (Mtb). HU is essential for Mtb survival and is one of the most abundant NAPs. It differs from other eubacterial HU proteins in having a long, flexible lysine- and arginine-rich carboxy-terminal domain. Lsr2 of Mtb is the functional analogue of the bacterial NAP commonly called H-NS. Lsr2 binds to and regulates expression of A/T-rich portions of the otherwise G/C-rich mycobacterial chromosome. Here, we demonstrate that HU and Lsr2 interact to form a complex. The interaction occurs primarily through the flexible carboxy-terminal domain of HU and the acidic amino-terminal domain of Lsr2. The resulting complex, upon binding to DNA, forms thick nucleoprotein rods, in contrast to the DNA bridging seen with Lsr2 and the DNA compaction seen with HU. Furthermore, transcription assays indicate that the HU-Lsr2 complex is a regulator of gene expression. This physical and functional interaction between two NAPs, which has not been reported previously, is likely to be important for DNA organization and gene expression in Mtb and perhaps other bacterial species.

Pharmacogenetic investigation of efficacy response to mepolizumab in eosinophilic granulomatosis with polyangiitis.

Treatment of patients with the rare disease eosinophilic granulomatosis with polyangiitis (EGPA) with mepolizumab, a monoclonal antibody to interleukin-5 (IL-5) that reduces blood eosinophil counts, as an add-on therapy to glucocorticoid treatment, results in more accrued weeks in remission, reductions in glucocorticoid use and reductions in relapse rate. However, treatment response varies across a continuum. Therefore, to investigate if large genetic effects could identify responders, the impact of genetic variants on efficacy in EGPA subjects taking mepolizumab and glucocorticoids was assessed in this post hoc study. Using linear regression and a negative binomial model, genetic variant association with three endpoints (accrued duration of remission, average oral glucocorticoid dose, and frequency of relapse) was tested in 61 EGPA subjects dosed with mepolizumab from MIRRA, a phase 3 trial. Candidate gene and genome-wide approaches were used. The candidate gene analysis was designed to investigate drug target effects with eight gene regions selected that were focused on the intersection of the glucocorticoid response (steroidal response) and IL-5 response mechanisms and recognizing potential overlap between EGPA and severe eosinophilic asthma diseases for which mepolizumab is used. The sample size was insufficient to enable testing of rare variants for effects. No genetic variant from either the candidate gene analysis or the GWAS associated with any endpoint. Thresholds to declare significance were p < 0.0008 (candidate variant) and p < 2.5 × 10-8 (genome-wide) analyses. Large genetic effects on mepolizumab-treatment response were not identified which could help differentiate responders from non-responders.

Sex Drives Dimorphic Immune Responses to Viral Infections.

New attention to sexual dimorphism in normal mammalian physiology and disease has uncovered a previously unappreciated breadth of mechanisms by which females and males differentially exhibit quantitative phenotypes. Thus, in addition to the established modifying effects of hormones, which prenatally and postpubertally pattern cells and tissues in a sexually dimorphic fashion, sex differences are caused by extragonadal and dosage effects of genes encoded on sex chromosomes. Sex differences in immune responses, especially during autoimmunity, have been studied predominantly within the context of sex hormone effects. More recently, immune response genes have been localized to sex chromosomes themselves or found to be regulated by sex chromosome genes. Thus, understanding how sex impacts immunity requires the elucidation of complex interactions among sex hormones, sex chromosomes, and immune response genes. In this Brief Review, we discuss current knowledge and new insights into these intricate relationships in the context of viral infections.

A Case of Life-threatening Amlodipine and Atenolol Overdose.

Treating a patient of amlodipine-atenolol poisoning is nightmare for a physician. In high dose both the drugs individually cause severe bradycardia and hypotension. In combination they cause severe cardiovascular depression. Here we report a case of 66-year-old obese, hypertensive, depressed male, who presented to emergency 9 hours after consumption of 25 tablets of amlodipine-atenolol (5 mg+50 mg). On evaluation, he had refractory bradycardia, hypotension and acute kidney injury (AKI). Eventually he developed cardiac arrest. He was revived after 5 minutes of cardio-pulmonary resuscitation (CPR). He was successfully managed with gastric lavage, fluids, inotropes, atropine, isoprenaline and subsequently with calcium gluconate infusion, high-dose insulin euglycemia therapy (HIET) and lipid emulsion therapy. Glucagon infusion was also planned but it was not available. Patient hemodynamics improved and on 8th day he got the discharge. Our case exemplifies the importance of timely and aggressive management of lethal overdose of amlodipine-atenolol poisoning. How to cite this article: Tale S, Kumar M, Ghosh S, Bhalla A. A Case of Life-threatening Amlodipine and Atenolol Overdose. Indian J Crit Care Med 2019;23(6):281-283.

Bioenergetic regulation of microglia.

Microglia have diverse actions, ranging from synapse pruning in development to cytotoxic effects in disease. Brain energy metabolism and substrate availability vary under normal and disease states, but how these variations influence microglial function is relatively unknown. Microglia, like most other cell types, express the full complement of gene products required for both glycolytic and oxidative metabolism. Evidence suggests that microglia increase aerobic glycolysis and decrease respiration when activated by various stimuli. Mitochondrial function, glucose availability, and glycolytic rate influence pro-inflammatory gene expression at both transcriptional and post-translational levels. These effects are mediated through CtBP, an NADH-sensitive transcriptional co-repressor; through effects on NLRP3 inflammasome assembly and caspase-1 activation; through formation of advanced glycation end-products; and by less well-defined mechanisms. In addition to these transcriptional effects, microglial glucose metabolism is also required for superoxide production by NADPH oxidase, as glucose is the obligate substrate for regenerating NADPH in the hexose monophosphate shunt. Microglia also metabolize acetoacetate and ß-hydroxybutyrate, which are generated during fasting or ketogenic diet, and respond to these ketones as metabolic signals. ß-Hydroxybutyrate inhibits histone de-acetylases and activates microglial GRP109A receptors. These actions suppress microglia activation after brain injury and promote neuroprotective microglia phenotypes. As our understanding of microglial activation matures, additional links between energy metabolism and microglial function are likely to be identified.

No evidence of large genetic effects on steroid response in asthma patients.

BACKGROUND: Inhaled corticosteroids (ICSs) are considered the most effective anti-inflammatory therapy for asthma control and management; however, there is substantial treatment response variability. OBJECTIVE: We sought to identify genetic markers of ICS response by conducting the largest pharmacogenetic investigation to date in 2672 ICS-treated patients with asthma. METHODS: Genotyping and imputation was performed in fluticasone furoate (FF) or fluticasone propionate-treated patients with asthma from 3 phase IIB and 4 phase IIIA randomized, double-blind, placebo-controlled, parallel group, multicenter studies. The primary end point analyzed was change in trough FEV1 (ΔFEV1) from baseline to 8 to 12 weeks of treatment. RESULTS: More than 9.8 million common genetic variants (minor allele frequency ≥ 1%) were analyzed to test for association with ΔFEV1. No genetic variant met the prespecified threshold for statistical significance. CONCLUSIONS: This study provides no evidence to confirm previously reported associations between candidate genetic variants and ICS response (ΔFEV1) in patients with asthma. In addition, no variant satisfied the criterion for genome-wide significance in our study. Common genetic variants are therefore unlikely to prove useful as predictive biomarkers of ICS response in patients with asthma.

A comparative analysis of salivary factors and maxillary denture retention in different arch forms: An in vivo study.

AIMS: This study aims to find the effect of change in different salivary factors before and after complete denture insertion and to measure the maxillary denture retention in different arch forms. MATERIALS AND METHODS: Thirty completely edentulous individuals (10 each of square, tapered, and ovoid arch form of maxilla) belonging to the age group of 40-70 years were selected. Salivary factors (flow, density, pH, viscosity, and total protein) were evaluated before and after denture insertion. Retention of maxillary denture was measured in all the different arch forms. STATISTICAL ANALYSIS: Student's independent sample's t-test was applied. The correlation was analyzed by Pearson's correlation analysis. RESULTS: While mean flow rate and pH of saliva increased, mean viscosity, total protein, and density of saliva decreased after maxillary complete denture insertion. A positive correlation was found between retention and total maxillary basal surface area. Retention value was found to be greatest in square type and least in tapered type. CONCLUSIONS: Complete denture acts as a mechanical stimulant thus increasing flow rate and pH immediately after complete denture insertion. Density, total protein, and viscosity of saliva decreased after complete denture insertion which may be due to increase in water content of saliva. The retention of maxillary complete denture does not seem to depend on the rate of change of the salivary factors, before and after complete denture insertion. Total basal surface area and maxillary denture retention values were highest in square arch form and least in tapered arch form.

A study on the accuracy of horizontal condylar guidance values in edentulous patients using preprosthetic diagnostic radiographs.

CONTEXT: Determination of horizontal condylar guidance (HCG) by various clinical and radiographic methods was performed by several investigators. If a correlation between HCG values using lateral radiographic tracing and protrusive interocclusal records can be established, the necessity of performing elaborate recording procedures can be eliminated. AIMS: The aim of this study is to evaluate and to compare the correlation between HCG values in edentulous people using the protrusive interocclusal records mounted on a semi-adjustable articulator with the manual tracing of panoramic radiograph and lateral cephalogram. MATERIALS AND METHODS: A total of 20 completely edentulous individuals of either sex from 45 to 75 years (mean age 63.15 years) fulfilling the inclusion criteria were included in this in vivo study. In all the participants, HCG angles were determined clinically using protrusive interocclusal records and semi-adjustable articulator after intraoral gothic arch tracing. Radiographically, it was obtained by cephalometric tracing of panoramic radiograph and lateral cephalogram. RESULTS: The present study shows mean HCG ± standard deviation (SD) of 28.17° ± 5.99° for interocclusal protrusive record while cephalometric tracing method yielded HCG ± SD of 38.95° ± 4.77° and 35.2° ± 4.94° for lateral cephalogram and orthopantomogram, respectively. A statistically significant positive correlation (P < 0.0001) was found among these three methods. CONCLUSION: HCG can be successfully determined in edentulous participants by using three aforementioned methods. HCG values from cephalometric tracing of diagnostic radiographs can be used as an adjunct to the clinical method but cannot be used independently for programming a semi-adjustable articulator.