Shared and distinct genetics of pure type 1 diabetes and type 1 diabetes with celiac disease, homology in their auto-antigens and immune dysregulation states: a study from North India.

AIM: This study was undertaken to explicate the shared and distinctive genetic susceptibility and immune dysfunction in patients with T1D alone and T1D with CD (T1D + CD). METHODS: A total of 100 T1D, 50 T1D + CD and 150 healthy controls were recruited. HLA-DRB1/DQB1 alleles were determined by PCR-sequence-specific primer method, SNP genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP-array and genotyping for INS-23 Hph1 A/T was done by RFLP. Autoantibodies and cytokine estimation was done by ELISA. Immune-regulation was analysed by flow-cytometry. Clustering of autoantigen epitopes was done by epitope cluster analytical tool. RESULTS: Both T1D alone and T1D + CD had a shared association of DRB1*03:01, DRB1*04, DRB3*01:07/15 and DQB1*02. DRB3*01:07/15 confers the highest risk for T1D with relative risk of 11.32 (5.74-22.31). Non-HLA gene polymorphisms PTPN22 and INS could discriminate between T1D and T1D + CD. T1D + CD have significantly higher titers of autoantibodies, expression of costimulatory molecules on CD4 and CD8 cells, and cytokine IL-17A and TGF-ß1 levels compared to T1D patients. Epitopes from immunodominant regions of autoantigens of T1D and CD clustered together with 40% homology. CONCLUSION: Same HLA genes provide susceptibility for both T1D and CD. Non-HLA genes CTLA4, PTPN22 and INS provide further susceptibility while different polymorphisms in PTPN22 and INS can discriminate between T1D and T1D + CD. Epitope homology between autoantigens of two diseases further encourages the two diseases to occur together. The T1D + CD being more common in females along with co-existence of thyroid autoimmunity, and have more immune dysregulated state than T1D alone.

Sarcopenia is common in ulcerative colitis and correlates with disease activity.

BACKGROUND/AIMS: Association of sarcopenia with disease severity in ulcerative colitis (UC) is not clearly defined. We planned to estimate the prevalence of sarcopenia in patients with UC as per the revised definition and its relation with the disease severity. METHODS: A cross-sectional assessment of sarcopenia in patients with UC was performed. Disease activity was graded according to complete Mayo score. Hand grip strength was assessed with Jamar hand dynamometer, muscle mass using a dual energy X-ray absorptiometry scan, and physical performance with 4-m walk test. Sarcopenia was defined as a reduction of both muscle mass and strength. Severe sarcopenia was defined as reduced gait speed in presence of sarcopenia. RESULTS: Of 114 patients (62 males, mean age: 36.49±12.41 years), 32 (28%) were in remission, 46 (40.4%) had mild-moderate activity, and 36 (31.6%) had severe UC. Forty-three patients (37.7%) had probable sarcopenia, 25 (21.9%) had sarcopenia, and 14 (12.2%) had severe sarcopenia. Prevalence of sarcopenia was higher in active disease (2 in remission, 6 in active, and 17 in severe, P<0.001). Of 14 with severe sarcopenia, 13 had severe UC while 1 had moderate UC. On multivariate analysis, lower body mass index and higher Mayo score were associated with sarcopenia. Of 37 patients with acute severe colitis, 16 had sarcopenia. Requirement of second-line therapy was similar between patients with and without sarcopenia. On follow-up (median: 18 months), there was a non-significant higher rate of major adverse events in those with sarcopenia (47.4% vs. 33.8%, P=0.273). CONCLUSIONS: Sarcopenia and severe sarcopenia in UC correlate with the disease activity.

Do vitamin D levels or supplementation play A role in COVID-19 outcomes?-a narrative review.

BACKGROUND AND OBJECTIVE: Hypovitaminosis D has been proposed as a risk factor for increased susceptibility to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and severe outcomes in coronavirus disease 2019 (COVID-19). Likewise, vitamin D supplementation has been proposed as an effective means for preventing and improving clinical outcomes in COVID-19. Nevertheless, available data are markedly inconsistent and contradictory. Considering the heterogeneity in the available clinical evidence, we planned to undertake a narrative review and provide a precise summary of the role of vitamin D in COVID-19. METHODS: PubMed/MEDLINE database was searched from inception till September 30, 2023 using appropriate MeSH terms. The initial search revealed 900 results. Thereafter, titles and abstracts were scanned and commentaries, letters, and editorials were excluded. Relevant observational studies and clinical trials/randomized controlled trials (RCTs) were full-text assessed and pertinent data were extracted for this narrative review. KEY CONTENT AND FINDINGS: Data from observational and ecological studies suggest that hypovitaminosis D is associated with a higher risk of acquiring COVID-19. Similarly, evidence support a negative association between 25-hydroxyvitamin D levels and COVID-19 severity, nevertheless, causality remains to be established. With regard to vitamin D supplementation and COVID-19-related health outcomes, data from observational studies and RCTs are contradictory. Even in moderate-to-severe/severe COVID-19, vitamin D supplementation has not been shown to be beneficial. Besides, data suggest that vitamin D levels might alter COVID-19 vaccine efficacy and be associated with long COVID. CONCLUSIONS: Vitamin D deficiency is linked to an increased risk of acquiring SARS-CoV-2 infection and poor COVID-19 prognosis, however, available evidence with regard to improved clinical outcomes with vitamin D supplementation is inconsistent.

AGEs accumulation with vascular complications, glycemic control and metabolic syndrome: A narrative review.

BACKGROUND: Multiple pathogenetic mechanisms are involved in the genesis of various microvascular and macrovascular complications of diabetes mellitus. Of all these, advanced glycation end products (AGEs) have been strongly implicated. OBJECTIVES: The present narrative review aims to summarize the available literature on the genesis of AGEs and their potential role in the causation of both micro- and macrovascular complications of diabetes mellitus. RESULTS: Uncontrolled hyperglycemia triggers the formation of AGEs through non-enzymatic glycation reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs accumulate in bloodstream and bodily tissues under chronic hyperglycemia. AGEs create irreversible cross-linkages of various intra- and extracellular molecules and activate the receptor for advanced glycation end products (RAGE), which stimulates downstream signaling pathways that generate reactive oxygen species (ROS) and contribute to oxidative stress. Additionally, intracellular glycation of mitochondrial respiratory chain proteins by AGEs contributes to the further generation of ROS, which, in turn, sets a vicious cycle that further promotes the production of endogenous AGEs. Through these pathways, AGEs play a principal role in the pathogenesis of various diabetic complications, including diabetic retinopathy, nephropathy, neuropathy, bone disease, atherosclerosis and non-alcoholic fatty liver disease. Multiple clinical studies and meta-analyses have revealed a positive association between tissue or circulating levels of AGEs and development of various diabetic complications. Besides, exogenous AGEs, primarily those derived from diets, promote insulin resistance, obesity, and metabolic syndrome. CONCLUSIONS: AGEs, triggered by chronic hyperglycemia, play a pivotal role in the pathogenesis of various complications of diabetes mellitus.

Drug-induced osteopetrosis.

Osteopetrosis (OPT) denotes the consequences from failure of osteoclasts to resorb bone and chondroclasts to remove calcified physeal cartilage throughout growth. Resulting impairment of skeletal modeling, remodeling, and growth compromises widening of medullary spaces, formation of the skull, and expansion of cranial foramina. Thus, myelophthisic anemia, raised intracranial pressure, and cranial nerve palsies complicate OPT when severe. Osteopetrotic bones fracture due to misshaping, failure of remodeling to weave the collagenous matrix of cortical osteons and trabeculae, persistence of mineralized growth plate cartilage, "hardening" of hydroxyapatite crystals, and delayed healing of skeletal microcracks. Teeth may fail to erupt. Now it is widely appreciated that OPT is caused by germline loss-of-function mutation(s) usually of genes involved in osteoclast function, but especially rarely of genes necessary for osteoclast formation. Additionally, however, in 2003 we published a case report demonstrating that prolonged excessive dosing during childhood of the antiresorptive aminobisphosphonate pamidronate can sufficiently block osteoclast and chondroclast activity to recapitulate the skeletal features of OPT. Herein, we include further evidence of drug-induced OPT by illustrating osteopetrotic skeletal changes from repeated administration of high doses of the aminobisphosphonate zoledronic acid (zoledronate) given to children with osteogenesis imperfecta.

Incidence and risk factors for dysglycaemia in Asian-Indians: a 10-year population-based prospective cohort study.

BACKGROUND: Diabetes prevalence estimates suggest an increasing trend in South-East Asia region, but studies on its incidence are limited. The current study aims to estimate the incidence of type 2 diabetes and pre-diabetes in a population-based cohort from India. METHODS: A subset of Chandigarh Urban Diabetes Study cohort (n=1878) with normoglycaemia or pre-diabetes at baseline was prospectively followed after a median of 11 (0.5-11) years. Diabetes and pre-diabetes were diagnosed as per WHO guidelines. The incidence with 95% CI was calculated in 1000 person-years and Cox proportional hazard model was used to find the association between the risk factors and progression to pre-diabetes and diabetes. RESULTS: The incidence of diabetes, pre-diabetes and dysglycaemia (either pre-diabetes or diabetes) was 21.6 (17.8-26.1), 18.8 (14.8-23.4) and 31.7 (26.5-37.6) per 1000 person-years, respectively. Age (HR 1.02, 95% CI 1.01 to 1.04), family history of diabetes (HR 1.56, 95% CI 1.09 to 2.25) and sedentary lifestyle (HR 1.51, 95% CI 1.05 to 2.17) predicted conversion from normoglycaemia to dysglycaemia, while obesity (HR 2.43, 95% CI 1.21 to 4.89) predicted conversion from pre-diabetes to diabetes. CONCLUSION: A high incidence of diabetes and pre-diabetes in Asian-Indians suggests a faster conversion rate to dysglycaemia, which is partly explained by sedentary lifestyle and consequent obesity in these individuals. The high incidence rates call for a pressing need for public health interventions targeting modifiable risk factors.

Immune Control of Avian Influenza Virus Infection and Its Vaccine Development.

The avian influenza A virus (AIV) is naturally prevalent in aquatic birds, infecting different avian species and transmitting from birds to humans. Both AIVs, the H5N1 and H7N9 viruses, have the potential to infect humans, causing an acute influenza disease syndrome in humans, and are a possible pandemic threat. AIV H5N1 is highly pathogenic, whereas AIV H7N9 has comparatively low pathogenicity. A clear insight into the disease pathogenesis is significant to understand the host's immunological response, which in turn facilitates the design of the control and prevention strategies. In this review, we aim to provide comprehensive details on the pathogenesis and clinical features of the disease. Moreover, the innate and adaptive immunological responses to AIV and the recent studies conducted on the CD8+ T cell immunity against AIVs are detailed upon. Further, the current status and advancement in the development of AIV vaccines, along with the challenges, are also discussed. The information provided will be helpful in combating the transmission of AIV from birds to humans and, thus, preventing severe outbreaks leading to pandemics worldwide.

Treatment outcomes of adjuvant radiotherapy in adrenocortical carcinoma - A 13-years experience from a tertiary care centre.

Purpose: Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignant neoplasm, usually diagnosed in advanced stage. Role and efficacy of adjuvant radiotherapy has not been well defined. The objective of this study is to describe the various clinical characteristics and prognostic factors affecting the survival of ACC along with the role radiotherapy on overall survival and relapse free survival. Methods: A retrospective analysis of 30 patients registered between 2007 and 2019 was carried out. The medical records containing clinical and treatment details were analysed. Data was analysed using SPSS 25.0. Survival curves were computed using Kaplan-Meier method. Univariate and multivariate analyses were performed to analyze the prognostic factors affecting the outcome. A p value of less than 0.05 was considered to be statistically significant. Results: The median age of patients was 37.5 years (range, 5-72 years). 20 patients were females. Twenty-six patients had advanced stage (III/IV) disease while only four patients presented in early stage. Twenty-six patients underwent total adrenalectomy. Eighty three percent patients received adjuvant radiation therapy. The median follow up was 35.5 months (range, 7 monthss-132months). The estimated three- and 5-years overall survival (OS) was 67.2% and 23.3%, respectively. Capsular invasion and positive margins were the independent prognostic factors influencing both OS and relapse free survival (RFS). Out of 25 patients who received adjuvant radiation, only three patients had local relapse. Conclusion: ACC is a rare and aggressive neoplasm with majority of patients presenting in advanced stage. Surgical resection with negative margins remains the mainstay of treatment. Capsular invasion and positive margins are independent prognostic factors for survival. Adjuvant radiation reduces the risk of local relapse and is well tolerated. Radiation can be used effectively in adjuvant and palliative settings in ACC.

The Role of Genetic Analysis in Demystifying the Diagnosis in a Middle-Aged Male Presenting With Proximal Muscle Weakness and Sclerotic-Lytic Skeletal Lesions.

Paget's disease of bone (PDB) usually presents with bone pain and deformities. Herein, we describe a case of PDB who presented with gradually progressive quadriparesis. A man in his forties presented with gradually progressive proximal muscle weakness involving all four limbs. The patient had an elevated serum alkaline phosphatase level and osteosclerosis at various skeletal sites in a radiological skeletal survey. 18F-fluorodeoxyglucose (FDG) PET-CT showed FDG-avid sclerotic-lytic lesions at multiple skeletal sites. Histopathology evaluation of bone and muscle biopsy specimens revealed PDB and inclusion body myopathy (IBM) with neurogenic atrophy, respectively. A diagnosis of IBM associated with PDB without frontotemporal dementia (IBMPFD) was suspected and confirmed by exome sequencing, which revealed a heterozygous mutation in the VCP gene. The bone disease responded to zoledronate administration. A high index of suspicion for IBMPFD should be kept in mind in any patient with PDB presenting with proximal muscle weakness.

Demystifying the Relevance of Size Amongst Macro- and Micro-Corticotropinoma: Experience in 206 Patients.

Objective: In individuals with adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome (CS), to estimate the differences between micro-corticotropinoma (size ≤6 mm and 6-10 mm), macro-corticotropinoma (>10 mm) and ectopic Cushing's syndrome (ECS), in relation to their epidemiological, clinical and biochemical parameters. Methods: In individuals with CS, the clinical and hormonal parameters, and magnetic resonance imaging of sella were collected from 1984 to 2019. A total of 138 cases of micro-corticotropinoma, 47 cases of macro-corticotropinoma and 21 cases of ECS were compared. Results: Except for size, there were no differences in biochemical and hormonal parameters of macro- and micro-corticotropinoma, irrespective of their size (≤6 mm, 6-10 mm and >10 mm). In comparison to Cushing's disease (CD), individuals with ECS had a male predominance (F:M ratio of 2.4:1 vs. 0.5:1), shorter duration from onset of symptoms to diagnosis (24 vs. 12 months). They also had a higher ACTH (139 vs. 65.8 pg/ml), 0800h cortisol (1200 vs. 880 nmol/l), 2300h cortisol (1100 vs. 700 nmol/l) and cortisol levels after high dose dexamethasone suppression test (1050 vs. 244.5 nmol/l). Conclusion: The biochemical phenotype of macro-corticotropinoma resembles that of micro-corticotropinoma despite their larger tumour size, suggesting that the former is relatively less functional. Micro-corticotropinoma ≤6 mm and 6-10 mm have a similar clinical and biochemical profile. As compare to CD, ECS is characterised by a higher disease burden as reflected in their higher cortisol, more autonomicity and loss of rhythmicity.

Age and Disease Duration Independent Cardiac Autonomic Neuropathy in Patients with Diabetic Foot Complications: Case-Control Study.

Introduction: Cardiac autonomic neuropathy (CAN) in people with diabetes is associated with high mortality. We aimed to study age and disease duration, independent prevalence of CAN in people with diabetic foot complications. Methods: 530 patients with diabetes were screened to undergo CAN assessment (automated CANS-analyser). CAN was defined as "early", "definite," or "severe" according to the Toronto consensus. History pertaining to autonomic symptoms, prior cardiovascular events (CVE), and assessment for peripheral neuropathy was done. Participants were grouped into those with diabetic foot complication (group A, n = 82) [Charcot foot (n = 42), diabetic foot ulcer (n = 40)]; with DPN without foot complications (group B, n = 82); and without DPN or foot complications (group C, n = 82). Results: Symptoms of autonomic dysfunction were prominent in people with foot complications than the other groups. Resting heart rate was significantly greater in those with foot complications [99.89 ± 26.71 (group A) vs. 86.99 ± 22.24 (group B) vs. 88.32 ± 17.08 (group C); P = 0.001]. The prevalence of CAN was 75.6% in group A (51.2% early, 12.2% definite, 12.2% severe), 57.2% in group B (45.1% early, 12.2% severe) and 58.5% in group C (43.9% early, 1.2% definite, 13.4% severe) (P = 0.002). Patients with foot complications were more likely to have CAN (75.6% vs. 57.9%, P < 0.001). Charcot foot had higher prevalence of CAN (78.6%) as compared with those with DFU (72.5%) or without DFU or DPN (57.9%), P < 0.001. Conclusion: CAN is present in more than two-third of patients with diabetes and foot complications with highest prevalence in Charcot neuroarthropathy.

Limited Invasive Protocol: Optimizing Diagnostic Modalities in Corticotropin Mediated Cushing Syndrome.

BACKGROUND: To limit the role of bilateral inferior petrosal sinus sampling (BIPSS) in distinguishing between Cushing disease (CD) and ectopic Cushing syndrome (ECS), recent reports have proposed a noninvasive approach based on a combination of biochemical testing and radiological imaging as an alternative to the conventional invasive strategy (CIS). However, this strategy requires further validation. The current study aimed to evaluate 2 limited invasive protocols (LIP-1 and LIP-2) in limiting the role of BIPSS while maintaining a diagnostic accuracy similar to that of CIS. METHODS: This was a single-center study conducted on individuals with corticotropin-dependent Cushing syndrome. The LIPs were based on performing high-dose dexamethasone suppression (>50% cut-off in first [LIP-1] and >80% in second [LIP-2]) and magnetic resonance imaging of the sella in all individuals and selective use of computed tomography of the chest and abdomen before BIPSS. These LIPs were evaluated for limiting the use of BIPSS, their accuracy, and cost in comparison to CIS. RESULTS: Of the 206 individuals, 114 (97 of CD and 21 of ECS) were eligible for the current study. Using LIP-1, LIP-2, and CIS, BIPSS could have been avoided in 62.3%, 35.9%, and 25.4% of individuals, respectively. The positive predictive value for CD using LIP-1 and LIP-2 was 98.9% and 100%, respectively. The cost per patient evaluated using LIP-1, LIP-2, and CIS was $602.21, $966.81, and $1107.78, respectively. CONCLUSION: LIPs represent an equally accurate, less invasive, and more cost-effective alternative to the CIS for distinguishing between CD and ECS.

Endocrine Follow-up During Post-Acute COVID-19: Practical Recommendations Based on Available Clinical Evidence.

OBJECTIVE: COVID-19 affects multiple endocrine organ systems during the disease course. However, follow-up data post-COVID-19 is scarce; hitherto available limited data suggest that most of the biochemical endocrine dysfunctions observed during acute phase of COVID-19 tend to improve after recovery. Hence, we aim to provide a rational approach toward endocrine follow-up of patients during post-acute COVID-19. METHODS: We performed a literature review across PubMed/MEDLINE database looking into the effects of COVID-19 on endocrine system and subsequent long-term endocrine sequelae. Accordingly, we have presented a practical set of recommendations regarding endocrine follow-up post-acute COVID-19. RESULTS: COVID-19 can lead to new-onset hyperglycemia/diabetes mellitus or worsening of dysglycemia in patients with preexisting diabetes mellitus. Hence, those with preexisting diabetes mellitus should ensure optimum glycemic control in the post-COVID-19 period. New-onset diabetes mellitus has been described post-acute COVID-19; hence, a selected group of patients (aged <70 years and those requiring intensive care unit admission) may be screened for the same at 3 months. Thyroid dysfunction (euthyroid sick syndrome and atypical thyroiditis) and adrenal insufficiency have been described in COVID-19; however, thyroid/adrenal functions usually normalize on follow-up; hence, widespread screening post-acute COVID-19 should not be recommended. Pituitary apoplexy and male hypogonadism have rarely been documented in COVID-19; therefore, appropriate follow-up may be undertaken as per clinical context. Hypocalcemia during COVID-19 is not uncommon; however, routine estimation of serum calcium post-COVID-19 is not warranted. CONCLUSION: The recommendations herein provide a rational approach that would be expected to guide physicians to better delineate and manage the endocrine sequelae during post-acute COVID-19.