"Trained Immunity" from Mycobacterium spp. exposure (BCG vaccination and environmental) may have an impact on the incidence of early childhood leukemia.

Preventive variables for childhood leukemia incidence (LI) remain unknown. Past assertions that childhood vaccinations, especially BCG, may be potentially protective have remained disputed for over five decades because of the lack of a unifying framework to explain variable outcomes in different studies. An examination of the early childhood LI for 2020 in European Region countries with supposedly similar underlying confounders but differential childhood vaccination coverage displays negative covariation with prevailing Mycobacterium spp. exposure in BCG-vaccinated children. The childhood LI in 0-4-year-old populations with >90% childhood BCG vaccination coverage is found to be strongly but negatively correlated with prevailing tuberculin immunoreactivity [r(24): -0.7868, p-value: < 0.0001]. No such correlation existed for the LI in 0-4-year-old populations without BCG vaccinations, though weak associations are hinted at by the available data for MCV2, PCV3, and DTP3 vaccinations. We hypothesize that early childhood BCG vaccination "priming" and subsequent "trained immunity" augmentation by "natural" boosting from Mycobacterium spp. exposure play a preventive and protective role in childhood LI. The non-consideration of prevailing "trained immunity" could have been a cause behind the conflicting outcomes in past studies. Exploratory studies, preferably performed in high-burden countries and controlling for the trained-immunity correlate and other potential confounders, would be warranted in order to establish a role for BCG vaccination and early-life immune training (or lack thereof) in childhood LI and help put the current controversy to rest.

Higher BCG-induced trained immunity prevalence predicts protection from COVID-19: Implications for ongoing BCG trials.

Endeavors to identify potentially protective variables for COVID-19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID-19 impact on populations to their Bacillus-Calmette-Guérin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within 5 years while most of the COVID-19 cases and deaths have occurred in aged with comorbidities. Since the supposed protection being investigated could come from heterologous 'trained immunity' (TI) conferred by exposure to Mycobacterium spp. (i.e., environmental and BCG), it is argued that the estimates of the prevalence of TI in populations currently available as latent tuberculosis infection (LTBI) prevalence would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (24), and erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher TI prevalence consistently display reduced COVID-19 impact as compared to their lower TI prevalence neighbors. The TI estimates of the populations not the BCG coverage per se, negatively correlated with pandemic phase-matched COVID-19 incidences (r(24): -0.79 to -0.57; p-value < .004), mortality (r(24): -0.63 to -0.45; p-value < .03), and interim case fatality rates (i-CFR) data. To decisively arrive at dependable conclusions about the potential protective benefit gained from BCG vaccination in COVID-19, the ongoing or planned randomized controlled trials should consciously consider including measures of TI as: (a) all individuals immunized do not respond equally, (b) small study groups from higher background TI could fail to indicate any protective effect.

Effect of Dipeptidyl Peptidase Inhibitors-4 and Sulfonylurea on Serum Adiponectin Levels in Patients with Newly Diagnosed Type 2 Diabetes Mellitus.

Diabetes mellitus implies a group of common metabolic disorders that share a phenotype of hyperglycemia. Peripheral insulin resistance and impaired insulin secretion forms two legs of this common, globally important non communicable disorder. Adiponectin is a hormone released by adipocytes which aids in enhancing insulin sensitivity, decreasing inflammatory mediators. Baseline adiponectin can predict diabetes and change in its value with change in metabolic parameters highlights the gravity of this molecule in more refined diagnosis and treatment of diabetes. AIMS: The objective was to ascertain change in adiponectin value in diabetics who were given either DPP-4 inhibitors or SU group drugs. Another objective was to find out correlation of serum adiponectin levels with various parameters involved in sugar and fat metabolism such as FBS, PPBS, HbA1c, LDL, HDL, VLDL, TG. MATERIAL: Total of 50 participants were taken, out of which 40 were diabetics and 10 were controls. They were selected using inclusion and exclusion criteria. Diabetics were divided into two arms with 20 participants each (a. dpp group b.su group). Clinical history, examination, sample collection was done. Serum adiponectin assay was performed using RayBio ELISA kit. OBSERVATION: Serum adiponectin levels in dpp group was higher at end of third month as compared to 0 month (45.9 +/- 5.9 vs. 39.8 +/- 4.1 mcg/dl; p<0.05). Likewise, adiponectin levels in su group was higher at end of third month as compared to 0 month (43.9 +/- 3.6 vs. 39.8 +/- 3.5 mcg/dl; p<0.05). CONCLUSION: Improvement in glycemic parameters (HbA1c, FBS, PPBS) is associated with rise in serum levels of adiponectin. General population possess higher levels of adiponectin as compared to diabetics. Adiponectin can serve as a marker for early diagnosis to diabetes. It can also aid in targeted therapy for metabolic disorders.

Potential for Further Mismanagement of Fever During COVID-19 Pandemic: Possible Causes and Impacts.

Fever remains an integral part of acute infectious diseases management, especially for those without effective therapeutics, but the widespread myths about "fevers" and the presence of confusing guidelines from different agencies, which have heightened during the coronavirus disease 2019 (COVID-19) pandemic and are open to alternate interpretation, could deny whole populations the benefits of fever. Guidelines suggesting antipyresis for 37.8-39°C fever are concerning as 39°C boosts the protective heat-shock and immune response (humoral, cell-mediated, and nutritional) whereas ≥40°C initiates/enhances the antiviral responses and restricts high-temperature adapted pathogens, e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strains of influenza, and measles. Urgent attention is accordingly needed to address the situation because of the potential public health consequences of the existence of conflicting guidelines in the public domain. We have in this article attempted to restate the benefits of fever in disease resolution, dispel myths, and underline the need for alignment of national treatment guidelines with that of the WHO, to promote appropriate practices and reduce the morbidity and mortality from infectious diseases, such as COVID-19.

CD300a Receptor Blocking Enhances Early Clearance of Leishmania donovani From Its Mammalian Host Through Modulation of Effector Functions of Phagocytic and Antigen Experienced T Cells.

The parasites of the genus Leishmania survive and proliferate in the host phagocytic cells by taking control over their microbicidal functions. The parasite also promotes differentiation of antigen-specific anti-inflammatory cytokines producing effector T cells, which eventually results in disease pathogenesis. The mechanisms that parasites employ to dominate host adaptive immunity are largely unknown. For the first time, we report that L. donovani, which causes visceral leishmaniasis in the Indian subcontinent, upregulates the expression of an immune inhibitory receptor i.e., CD300a on antigen presenting and phagocytic cells to dampen their effector functions. The blocking of CD300a signals in leishmania antigens activated macrophages and dendritic cells enhanced the production of nitric oxide, pro-inflammatory cytokines along with MHCI/II genes expression, and reduced parasitic uptake. Further, the abrogation of CD300a signals in Leishmania infected mice benefited antigen-experienced, i.e., CD4+CD44+ and CD8+CD44+ T cells to acquire more pro-inflammatory cytokines producing phenotypes and helped in the early clearance of parasites from their visceral organs. The CD300a receptor blocking also enhanced the conversion of CD4+ T effectors cells to their memory phenotypes i.e., CCR7high CD62Lhigh up to 1.6 and 1.9 fold after 14 and 21 days post-infection, respectively. These findings implicate that CD300a is an important determinant of host phagocytic cells functions and T cells differentiation against Leishmania antigens.

The CD200-CD200R cross-talk helps Leishmania donovani to down regulate macrophage and CD4+CD44+ T cells effector functions in an NFκB independent manner.

The lacuna in the knowledge of immunobiology, especially in visceral infections that are fatal if left untreated, are a major hurdle in getting a vaccine candidate for leishmaniasis. Till date, only a few drugs are available to combat human leishmaniasis and a vaccine candidate either prophylactic or preventive is still awaited. Therefore, identification of host and parasitic factors involved in the regulation of specific immune mechanisms are essentially needed. In this study, we observed that CD200-CD200R immune inhibitory axis regulates host macrophages effectors properties and helps antigen experienced T cells (CD4+CD44+ T cells) to acquire anti-inflammatory cytokines (IL-4, IL-10, TGF-ß, IL-27) producing abilities in an NFkB independent manner. After CD200 blocking the macrophages effectively inhibited proliferation of Leishmania amastigotes and also induced the production of IL-12, IFN-γ, TNF-α and nitric oxide (NOx). Further, the blocking of CD200 signaling also restored macrophages MHC-II expression and helped CD4+CD44+ T cells to produce pro-inflammatory cytokines like IL-2, IL-12 and IFN-γ. The finding of this study suggested the importance of immune inhibitory mechanisms in controlling Leishmania growth and survival and therefore, requires more studies to understand its role in vaccine induced immunity.

The Novel Biomarkers in Diabetes.

According to International Diabetes Federation, the worldwide prevalence of impaired glucose tolerance (IGT) in adults is 318 million and is expected to reach 482 million by 2040. With increasing burden of prediabetes and their expectant progression in diabetes has compounded the problem. Now question is that how we can identify the subjects at high risk to develop prediabetic state and among them who will rapidly progress into diabetes? Once a person diagnosed to be a diabetic then there are only few marker which can depict development of diabetes related complications and also to help in preventing such diabetes related complication progression. In this article, we will review several biomarkers used to predict the risk of progression to prediabetes, diabetes states in context to their mechanism of action, sensitivity, specificity, advantages, disadvantages and association with dysglycemia. The risk stratification arising due to insulin resistance by novel biomarker will improve clinical outcome both in prediabetics and diabetics.

Evaluation of Plasma Homocysteine Levels in Patients of PCOS.

BACKGROUND: Homocysteinemia in PCOS may impair implantation by interfering with endometrial blood flow and has been documented to increase the adverse pregnancy outcome. AIMS: The objective was to evaluate the relationship between insulin resistance and serum homocysteine in subjects with polycystic ovarian syndrome (PCOS). MATERIAL AND METHODS: Cross sectional Case Control observational study done in Department of Obstetrics and Gynecology, KGMU Lucknow. Cases were 50 PCOS women as a study group and 40 women with infertility due to isolated male cause as a control group. Serum homocysteine levels compared in PCOS patients. RESULTS: Mean homocysteine raised in cases (11.8 ± 5.5µmol/L) than control (7.8 ± 2.2 µmol/L), p< 0.001 Considering 11 µmol/l cut off level for normal homocysteine, 36% of PCOS patients (18 of 50) and 10%of control (4 out of 40) had high homocysteine levels, p< 0.001. 8% of PCOS patients without insulin resistance (4 out of 50) had a high homocysteine level, while 28%of PCOS patients with insulin resistance (14 out of 50) had homocysteinemia. Mean plasma homocysteine level was very high in insulin resistant case group subjects (13.9 ± 5.6 µmol/L) than non insulin resistant subjects in case group (8.2 ± 2.7), p< 0.001. CONCLUSION: Insulin resistance and hyperinsulinaemia in patients with PCOS is associated with elevated plasma homocysteine This finding may have important implications in the short-term reproductive outcome, and the long-term cardiovascular complications associated with insulin-resistant PCOS.

A clinico-epidemiological study of cognitive function status of community-dwelling elderly.

BACKGROUND: Cognitive decline and dementia are an important problem affecting quality-of-life in elderly and their caregivers. There is regional variation in prevalence of cognitive decline as well as risk factors from region to region. AIM: The aim was to determine the prevalence of dementia and cognitive decline and its various risk factors in the elderly population of more than 60 years in Eastern Uttar Pradesh (India). MATERIALS AND METHODS: A camp-based study was conducted on rural population of Chiraigaon block of Varanasi district from February 2007 to May 2007. Block has 80 villages, of which 11 villages were randomly selected. Eleven camps were organized for elderly people in 11 randomly selected villages on predetermined dates. A total of 728 elderly persons of age >60 years were examined, interviewed and data thus collected was analyzed. Elderly who got Hindi-mini-mental state examination (HMSE) score developed by Ganguli based on the Indo-US Cross-National Dementia Epidemiology Study) score ≤23 were evaluated further and in those with confirmed cognitive and functional impairment, diagnosis of dementia was assigned according to Diagnostic and Statistical Manual for Mental Disorder fourth edition criteria after ruling out any psychiatric illness or delirium. Based on International Classification of Diseases-10 diagnostic criteria sub-categorization of dementia was done. RESULTS: Mean, median and 10(th) percentile of HMSE of the study population were 23.4, 24 and 17, respectively. About 14.6% elderly had scored <17. 42.9% of rural elderly population had HMSE score <23, 70.6% <27 and 27.7% between 23 and 27. Literate people had statistically significant higher mean HMSE score (26.1 ± 3.9) than illiterate people (22.9 ± 4.9). Other risk factors were female gender, malnutrition, and obesity. Prevalence of dementia was 2.74%; in male 2.70% and in female 2.80%. Most common type of dementia was Alzheimer (male 1.5%, female 1.5%) followed by vascular (male 1.2%, female 0.6%) and others 0.6% (male 0%, female 0.6%). CONCLUSIONS: Study showed that a very high percentage of rural elderly attending health camps had poor cognitive function score; though the prevalence of dementia was relatively low. Alzheimer dementia was most common, followed by vascular dementia, which was predominant in males. Illiteracy, age, and under-nutrition were the most important risk factors for poor cognitive function. Our study suggest that cut-off of HMSE score should be 17 (10(th) percentile) for illiterate population.

Persistent Hiccups-An Unusual Presentation of Bilateral Pheochromocytoma without Syndromic Association: A Case Report.

Pheochromocytoma is a rare catecholamine-producing tumor arising from chromaffin tissue in the adrenal medulla, occurring in less than 0.2 percent of patients with hypertension. The mean age at diagnosis is about 40 years. Pheochromocytomas are commonly inherited as features of multiple endocrine neoplasia type 2 or several other pheochromocytoma-associated syndromes and have variable clinical presentation. Among the presenting symptoms, episodes of palpitations, headaches, and profuse sweating are typical and constitute a classic triad. We report a case of a 17-year-old male patient with rare bilateral pheochromocytoma presenting with persistent hiccups for 4 months and blurring of vision for 1 week, later followed by hypertensive crisis. There was neither family history of pheochromocytoma nor any classic symptoms. Patient was diagnosed with bilateral pheochromocytoma without any syndromic association. But still this patient needs to be followed for future development of medullary carcinoma of thyroid because it could be an initial presentation of MEN 2A/2B/VHL syndromes. Our paper highlights the importance of maintaining a high level of suspicion for persistent hiccups and careful clinical screening for hypertension even in absence of associated syndromes of pheochromocytoma and classical symptoms to achieve prompt diagnosis and to avoid improper management.

Hepatocellular carcinoma presenting as polymyositis: a paraneoplastic syndrome.

Polymyositis as a paraneoplastic syndrome associated with hepatocellular carcinoma is quite rare; only a few cases have been reported. We report a case of a 50-year-old female who presented with subacute quadriparesis, neck muscle weakness, elevated creatinine phosphokinase, a myogenic pattern on the EMG and was diagnosed as having polymyositis, a paraneoplastic syndrome associated with hepatocellular carcinoma with negative hepatic viral markers and a positive ANA. Improvement in patient symptoms and areduction in creatinine phosphokinase, which occurred after lobectomy, supports this rare association.

Evaluation of delirium in elderly: a hospital-based study.

AIM: The study aimed to study the prevalence, etiologies, clinical profile and outcome of delirium in hospitalized elderly in medicine wards. METHODS: Four hundred elderly patients of more than 60years of age admitted with delirium in the emergency and medicine wards of Sir Sunderlal Hospital Varanasi, India, were evaluated and managed. The Hindi version of the Mini-Mental Status Examinations, a vernacular (Hindi) version of the Mini-Mental State Examination, was used for evaluation of cognitive function status of patients and Confusion Assessment Method (CAM), a screening instrument based on the third edition of the Diagnostic and Statistical Manual of Mental Disorders was used for diagnosis of delirium. RESULTS: A total of 400 hospitalized elderly delirious patients were included in the study aged 61-105years. The mean age of the subjects was 70.87±9.26years and 70.81±8.4years amongst males and females, respectively. The mortality rate was 14.75%. Out of nine CAM features, all the cases had all three essential features, 78.75% had four features, 58.5% had five features, 44.5% had six features and 9.25% had all nine features. There was a high prevalence of hypoactive delirium (65%) as compared to hyperactive (25%) or mixed (10%). Most common etiologies were sepsis followed by metabolic abnormalities. 70% had 2 or more etiologies. CONCLUSION: Sepsis and metabolic abnormalities were the most common etiologies of delirium in this study. The maximum patients had more than one etiology and this emphasizes the multifactorial nature of delirium and need for thorough evaluation to unravel them. Most of the causes were treatable and have favorable outcome (83% recovered).

IL-13 from Th2-type cells suppresses induction of antigen-specific Th1 immunity in a T-cell lymphoma.

Dalton's lymphoma (DL) is a transplantable T-cell lymphoma of spontaneous origin, characterized by highly invasive and immunosuppressive property. Progression of DL cells results into an imbalance of T helper type 1 (T(h)1)/T helper type 2 (T(h)2)-type cytokine in the host, which is partly responsible for DL-induced severe immunosuppression and DL cell progression. In this study, we have shown the role of IL-13 in the regulation of T(h)1 immunity in both normal healthy and DL-bearing host. IL-13 pre-treatment inhibits the induction of 2,4-dinitro-1-fluorobenzene-induced contact hypersensitivity and delayed-type hypersensitivity (DTH) in antigen-challenged mice, which have been confirmed by neutralizing IL-13 by systemic delivery of non-signaling decoy receptor IL-13Ralpha2. Furthermore, IL-13 neutralization enhances the splenocyte proliferation, which has been inhibited by IL-13 administration. Adoptive transfer of splenocyte from IL-13-pre-treated mice and macrophages incubated with IL-13 and pulsed with antigens suppresses the DTH as well in antigen-challenged recipient mice. In addition, it also suppresses the production of pro-inflammatory cytokine and C-C chemokine in DTH footpad. Furthermore, IL-13 neutralization not only enhances the DTH reaction but also increases longevity and survival of DL-bearing host, which suggests that blocking/inactivating systemic IL-13 enhances T(h)1 immunity, and therefore, effects to diminish IL-13 production may have therapeutic value in a host bearing T-cell lymphoma.

Autologous Hsp70 induces antigen specific Th1 immune responses in a murine T-cell lymphoma.

Heat Shock protein-70 derived from tumor cells is highly immunogenic and induces specific anti-tumor immune response by directly activating cytotoxic CD8(+) T cells. Additionally, Hsp70 is known to be a strong activator of antigen presenting cells and therefore, up regulates the production of pro-inflammatory cytokines and chemokines. In this study, we have shown the effect of tumor-derived Hsp70 on the induction of delayed type hypersensitivity reaction in a T cell lymphoma bearing mice. The autologous Hsp70 augments contact hypersensitivity and delayed type hypersensitivity responses in mice challenged with allergen in vehicle and antigens respectively. The adoptive transfer of splenocytes derived from Hsp70 immunized mice is able to enhance delayed type hypersensitivity response in antigen challenged normal and DL-bearing host. Furthermore, adoptive transfer of macrophages incubated with autologous Hsp70 also enhances DTH reactivity in mice. The pro-inflammatory cytokines and C-C chemokines are found to be elevated in the DTH footpad extract of antigen challenged normal and DL-bearing mice. Increased production of IFN-gamma and MIP-1alpha+/- suggest that autologous Hsp70 augments the recruitment of antigen specific Th1 cells, which further secretes pro-inflammatory cytokines and C-C chemokines mediating the hypersensitivity reaction upon challenge with antigens.