Co-existence of type 1 diabetes and other autoimmune ailments in subjects with autoimmune thyroid disorders.

BACKGROUND AND AIMS: Autoimmune thyroid dysfunction (AITD) is a significant autoimmune disorder affecting the population across age groups. The clustering of autoimmune diseases tends to occur within the same patients and families. Thus, this study aimed to determine the association of Type 1 diabetes and other autoimmune ailments in patients with autoimmune thyroid disorders. METHODS: We performed a cross-sectional study, evaluating 500 subjects with a diagnosis of AITD (130 with Graves' disease; 370 with Hashimoto's thyroiditis) on presentation to our tertiary care centre to ascertain the prevalence of associated autoimmune disorders. RESULTS: The frequency of Type 1 diabetes and other autoimmune disorders was 18.5% in Graves' disease and 27.8% in Hashimoto's thyroiditis patients. Coeliac disease (8.8%) (found in 6.9% of Graves' disease and 9.5% of Hashimoto's thyroiditis patients) and type 1 diabetes (7.8%) (found in 3.1% of Graves' disease and 9.5% of Hashimoto's thyroiditis patients) were the most common coexisting autoimmune disorders. Rheumatoid arthritis was the most common non-endocrine autoimmunity (2.8%). Female sex and duration of AITD more than five years were associated with increased odds of associated autoimmune disorders. CONCLUSION: A high prevalence of associated autoimmune disorders was observed in subjects with autoimmune thyroid dysfunction. We suggest the patients who remain symptomatic and those who develop other symptoms even with appropriate treatment undergo screening for associated autoimmune disorders, thus preventing a delay in diagnosis.

Cardiac Autonomic Modulation and Anti-Thyroid Peroxidase (TPO) Antibodies in Subclinical Hypothyroidism: Does a Correlation Exist?

BACKGROUND: Heart rate variability (HRV) reflects the balance between the sympathetic and parasympathetic divisions of the autonomic nervous system. Anti-thyroid antibodies like anti-TPO and anti-Thyroglobulin have long been associated with thyroid dysfunction and abnormal thyroid profile testing. Subclinical hypothyroidism (SCHypo) is characterized by elevated thyroid-stimulating hormone (TSH) with normal thyroid hormones. We hypothesize that autonomic function may be deranged in anti-TPO positive sub-clinical hypothyroid cases, even before the onset of overt hypothyroidism. OBJECTIVES: To investigate the association between anti-Thyroid Peroxidase antibodies (anti-TPOAb) positive SCHypo and sympathovagal imbalance (SVI), if any. METHODOLOGY: The study was conducted on the age and body mass index (BMI) matched subclinical hypothyroid patients (n=52) and healthy controls (n=20). The cardiac autonomic activity was assessed by short-term HRV in the time (SDNN, RMSSD, pNN50) and frequency domains (LFms2, HFms2, LFnu, HFnu, TP, and LF/HF ratio). Nonlinear geometric measures (SD1, SD2, SD1/SD2, TINN, HRV triangular index) were also evaluated. Biochemical evaluation of serum thyroid profile and anti-TPOAb was done in all the subjects. RESULTS: Decreased HRV was observed in the anti-TPOAb positive group when compared to the antibody-negative and control groups. Significant positive correlation of anti-TPOAb with TSH, LFnu, LF/HF and negative correlation with SDNN, RMSSD, pNN50, SD1, SD1/SD2, HFnu, and TP of HRV was observed. CONCLUSION: Anti-TPOAb positive SCHypo group exhibited modifications in HRV characterized by decreased parasympathetic modulation, as compared to controls. The findings were also suggestive of increased risk of autonomic dysfunction in TPOAb-positive patients, as compared to antibody negative. An increase in anti-TPO antibodies was significantly correlated with TSH and SVI in SCHypo patients.

Higher CNV Frequencies in Chromosome 14 of Girls With Turner Syndrome Phenotype.

CONTEXT: Precise genotype-phenotype correlations in Turner syndrome (TS) have not yet been deciphered. The chromosomal basis of the clinical TS phenotype in the absence of X chromosome aberrations on conventional karyotyping remains more and less unexplored. OBJECTIVE: To elucidate the high-resolution chromosomal picture and analyze the genotype-phenotype associations in girls with clinical phenotype of TS by chromosomal microarray. DESIGN AND PATIENTS: Cross sectional observational study conducted between October 2018 and January 2020 on 47 girls presenting the clinical TS phenotype and fulfilling the criteria for chromosomal analysis. SETTING: Outpatient department at Department of Endocrinology and the Molecular Research Lab at tertiary care teaching institution. RESULTS: The copy number variation (CNV) polymorphs were more frequent on autosomes than X chromosomes, and they were detected in 89.3%, 61.7%, and 92.8% of patients, respectively, on chromosome 14 or X or both. A total 445 and 64 CNV polymorphs were discovered on chromosome X and 14, respectively. The latter exhibited either gain at 14q32.33, loss at 14q11.2, or both. Karyotype was available for 27 patients; 55.6% of cases displayed X chromosome abnormalities while 44.4% cases had a normal karyotype. Functional interactomes of the genes that were present in chromosome 14 CNVs and those known to be associated with TS showed an overlap of 67% and enriched various development-related cellular pathways underlying TS phenotype. CONCLUSIONS: On high-resolution karyotype analysis, clinical phenotype of TS can be associated with CNV defects in autosomes, specifically chromosome 14 or X chromosome or both. The syndrome of chromosome 14 CNV defects with and without X-chromosomal defects clinically mimics TS and shares a common genomic network that deserves further investigations.

High throughput detection and genetic epidemiology of SARS-CoV-2 using COVIDSeq next-generation sequencing.

The rapid emergence of coronavirus disease 2019 (COVID-19) as a global pandemic affecting millions of individuals globally has necessitated sensitive and high-throughput approaches for the diagnosis, surveillance, and determining the genetic epidemiology of SARS-CoV-2. In the present study, we used the COVIDSeq protocol, which involves multiplex-PCR, barcoding, and sequencing of samples for high-throughput detection and deciphering the genetic epidemiology of SARS-CoV-2. We used the approach on 752 clinical samples in duplicates, amounting to a total of 1536 samples which could be sequenced on a single S4 sequencing flow cell on NovaSeq 6000. Our analysis suggests a high concordance between technical duplicates and a high concordance of detection of SARS-CoV-2 between the COVIDSeq as well as RT-PCR approaches. An in-depth analysis revealed a total of six samples in which COVIDSeq detected SARS-CoV-2 in high confidence which were negative in RT-PCR. Additionally, the assay could detect SARS-CoV-2 in 21 samples and 16 samples which were classified inconclusive and pan-sarbeco positive respectively suggesting that COVIDSeq could be used as a confirmatory test. The sequencing approach also enabled insights into the evolution and genetic epidemiology of the SARS-CoV-2 samples. The samples were classified into a total of 3 clades. This study reports two lineages B.1.112 and B.1.99 for the first time in India. This study also revealed 1,143 unique single nucleotide variants and added a total of 73 novel variants identified for the first time. To the best of our knowledge, this is the first report of the COVIDSeq approach for detection and genetic epidemiology of SARS-CoV-2. Our analysis suggests that COVIDSeq could be a potential high sensitivity assay for the detection of SARS-CoV-2, with an additional advantage of enabling the genetic epidemiology of SARS-CoV-2.

A Study on Impact of BPA in the Adipose Tissue Dysfunction (Adiposopathy) in Asian Indian Type 2 Diabetes Mellitus Subjects.

A surge to increase the production via usage of chemicals at both industrial and agricultural arena has forced humans to be routinely and imprudently exposed to a wide variety of endocrine disrupting chemicals. The overall aim of the study was to evaluate possible relation that might exist between bisphenol-A (BPA) and the adipose tissue hormones, and further impact on adiposopathy. In the present study, the role of BPA, an "endocrine disruptor" with respect to adiposopathy was evaluated in type 2 diabetes mellitus patients. For the study, 150 healthy control subjects and 150 newly diagnosed diabetes patients were recruited. Fasting venous blood samples was analyzed for several biochemical parameters such as serum glucose, lipid profile, insulin, adiponectin, leptin, TNF-α, IL-6, IL-1, free fatty acid. Concentrations of BPA were also measured both in control and diabetic subjects. Serum BPA concentration was found to be significantly higher in diabetic subjects in comparison to the control subjects. Levels of BPA were found to be positively correlated with BMI and WC in diabetic subjects. Also, it was found to be positively correlated with leptin and negatively correlated with adiponectin in diabetic subjects. Therefore, the current study suggested more deleterious effect of BPA on diabetes and its pathophysiology.

Bilateral Inferior Petrosal Sinus Sampling in Corticotropin-Dependent Cushing's Syndrome: A Single Center Experience from Western India.

OBJECTIVE: Efficacy of bilateral inferior petrosal sinus sampling (BIPSS) in corticotropin-dependent Cushing's syndrome (CS) for localization and lateralization of excess adrenocorticotropic hormone (ACTH) source, as compared to high-dose dexamethasone suppression test (HDDST) and magnetic resonance imaging (MRI) pituitary, respectively. METHODOLOGY: Thirteen patients with clinically and biochemically confirmed CS underwent HDDST, MRI pituitary, and BIPSS by an experienced team of intervention neurologist, neurosurgeon, and endocrinologist using percutaneous femoral vein approach. RESULTS: Of 13 patients (11 adults and two children) who underwent BIPSS, raised central to peripheral ACTH ratio was achieved in 12 cases, remaining one case being ectopic ACTH secretion (EAS). However, inter IPS gradient >1.4 was achieved in 11 (91.6%) of 12 Cushing's disease (CD) cases before vasopressin stimulation; and in 9 (75%) of 12 CD cases after vasopressin stimulation (P-value 0.583). HDDST suppression of more than 50% was present in only ten cases with CD, falsely negating CD in two cases (16.6%), sensitivity 83.3% and specificity 100%. MRI sella demonstrated pituitary microadenoma in 12 cases and macroadenoma in one case. Lateralization by BIPSS and MRI was concordant in 7 (58.3%) out of 12 cases with CD, with rate of remission after transsphenoidal surgery being higher in patients with concordant lateralization by BIPSS and MRI. CONCLUSIONS: BIPSS is an important investigation to distinguish CD and EAS. BIPSS was superior to HDDST for confirming the source of excess ACTH. Our findings favor the use of BIPSS for localization and pituitary MRI for lateralization of microadenoma.

Efficacy of Vyoshadi Guggulu and Shadushana Churna in the management of subclinical hypothyroidism: An open labelled randomized comparative pilot clinical trial.

Background: Subclinical hypothyroidism (SCH) is defined as a mildly reduced function of the thyroid gland having elevated serum thyroid-stimulating hormone (TSH) level and normal concentrations of free tri-iodothyronine (FT3), free tetra-iodothyronine (FT4), T3 and T4. It occurs due to "Agnimandya" (low metabolic activity) at the systemic and cellular level. Vyoshadi Guggulu and Shadushana Churna having its effect on Agni (a root cause of SCH) are expected to prevent overt hypothyroidism and revert subclinical stage to euthyroid. Aim: This study was planned to evaluate and compare the efficacy of Vyoshadi Guggulu and Shadushana Churna in the management of Dhatvagnimandya with special reference to sub-clinical hypothyroidism (SCH). Materials and methods: Patients having serum TSH levels between 5 and 10 mlU/L and normal T3 and T4 values were diagnosed as SCH. A total of 30 patients were registered and randomly divided into two groups. In group A, patients were treated with Vyoshadi Guggulu (6 g), while in group B with Shadushana Churna (3 g) twice a day after lunch and dinner for 60 days. The assessment was done through changes in baseline and after treatment values of serum TSH level. Outcomes of the trial were analyzed using SigmaStat 4.0 version (trial) software. Student's paired t-test was used for within-group assessment, while unpaired t-test was used for intergroup comparison of the normally distributed parametric data. Observations and Results: Ten patients in group A and 11 in group B could complete the course of treatment. The findings revealed that therapy in group A and B showed decrease of 16.61% (P = 0.0494) and 26.29% (P = 0.0140) in serum TSH, respectively, 1.80% (P = 0.025) and 1.36% (P = 0.019) decrease in body mass index (BMI), respectively. The decrease in TSH and BMI was statistically significant in each group. In comparison, the decrease in serum TSH (P = 0.384) and BMI (P = 0.677) was statistically insignificant. Conclusions: Vyoshadi Guggulu and Shadushana Churna are statistically equally effective to reduce serum TSH and BMI in the management of SCH.

Coexistence of Autoimmune Disorders and Type 1 Diabetes Mellitus in Children: An Observation from Western Part of India.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is associated with various autoimmune disorders like celiac disease, thyroid disorder, adrenal failure, etc. However, how common is this association in Indian children is not clearly known. OBJECTIVE: To assess the prevalence of other coexisting autoimmune disorders in children with T1DM. MATERIALS AND METHODS: In this cross-sectional study, patients requiring insulin and ketosis-prone diabetic and with history of diabetic ketoacidosis/undetectable fasting C-peptide levels were included. Beside demographic and clinical data, detailed biochemistry evaluations were performed. Celiac disease was diagnosed as per the ESPGHAN diagnostic criteria. ACTH stimulation test was done to confirm the adrenal insufficiency in patients with basal serum cortisol <5 µg/dL. Thyroid function test (TSH) and anti-TPO antibody were assessed in all patients. Screening for other autoimmune disorders was done only when clinically indicated or symptoms or family history was suggestive of presence of such disorder. RESULTS: Among 150 patients enrolled, 64.66% were males and mean age was 13.48 ± 3.29 years (range 3-18 years). Mean age at diagnosis of T1DM was 10.0 ± 3.63 years and duration of diabetes was 3.46 ± 3.18 years. The prevalence of antibodies positive against autoimmune diseases was anti-tTG IgA (20.7%), anti-TPO (33.7%), anti-CCP ab (1.3%), and ANA (0.7%). Significantly higher proportion of females had raised anti-TPO antibodies than males (47.2% vs. 25.8%, P = 0.006). Celiac disease was most common association (24.8%) followed by hypothyroidism (14.1%) and Grave's disease (3.3%). Significantly higher proportion of females had hypothyroidism than males (25.0% vs. 8.2%, respectively, P = 0.005). Prevalence of raised anti-tTG and anti-TPO did not differ significantly by the age (P = 0.841 and P = 0.067) or duration of T1DM (P = 0.493 and P = 0.399). CONCLUSION: In this part of country, celiac disease, hypothyroidism, and Graves's disease are common associations in children with T1DM.

Linear Analysis of Autonomic Activity and Its Correlation with Creatine Kinase-MB in Overt Thyroid Dysfunctions.

Autonomic activity may be deranged in thyroid dysfunctions and may lead to cardiovascular morbidity and mortality. Myopathy is a common manifestation in thyroid disorders and may be associated with raised serum creatine kinase (CK). We hypothesized that cardiovascular abnormality in thyroid dysfunction may manifest as raised CK-MB. This study was designed to investigate the correlation of CK and its isoform CK-MB with thyroid profile and linear parameters of heart rate variability (HRV). The study was conducted on 35 hypothyroid and hyperthyroid patients each, and 25 age-matched healthy controls. Autonomic activity was assessed by simple short term 5-min HRV. Biochemical evaluation of serum thyroid profile, CK-NAC and CK-MB were estimated in all the subjects. Our results demonstrated low HRV in hypo- as well as hyperthyroid patients. We observed significantly higher serum CK levels in hypothyroid patients when compared to hyperthyroids and controls. However, no significant differences were observed in CK-MB levels in the three groups. Significant positive correlation of CK with TSH and negative correlation with some HRV parameters (LF power, HF power, total power, SDNN, RMSSD) was observed in hypothyroid patients. Whereas correlation of CK-MB with thyroid profile as well as HRV parameters was non-significant in all the groups. Based on the CK and CK-MB findings and their correlation, we conclude that the cardiovascular changes seen in thyroid dysfunctions may primarily be due to autonomic imbalance without apparent cardiac muscle involvement. Whereas, raised CK levels indicate predominantly skeletal muscle involvement in hypothyroid patients.

Erratum to: Linear Analysis of Autonomic Activity and Its Correlation with Creatine Kinase-MB in Overt Thyroid Dysfunctions.

[This corrects the article DOI: 10.1007/s12291-017-0659-0.].

Advancement in nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia.

Cardiovascular diseases have been the major cause of mortality and morbidity all over the world accounting for more than 80% of the deaths from heart attacks and strokes. Hypercholesterolemia, an autosomal disorder of lipoprotein metabolism is one of the foremost causes of CVDs. An increased level of low-density lipoprotein cholesterol (LDL-C) in the plasma results in the rise of incidence rates in disease patients. Several conventional and combinational therapies have been proposed for lowering the LDL-C levels in the blood. These therapeutic agents are designed to target some crucial molecules that participates in the lipid metabolism such as apolipoprotein B, HMGCoA reductase, proprotein convertase subtilisin/kexin 9, etc. Although these therapies are effective but are associated with certain side effects. This article presents an overview on different conventional and nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia. Numerous nanomaterial-based therapies including polymeric nanoparticles, cationic lipids, liposomes, dendrimers and inorganic nanoparticles have been discussed in lowering the cholesterol level along with recent advancement in diagnosis and imaging.

Common variants of SLAMF1 and ITLN1 on 1q21 are associated with type 2 diabetes in Indian population.

Though multiple studies link chromosomal regions 1q21-q23 and 20q13 with type 2 diabetes, fine mapping of these regions is yet to confirm gene(s) explaining the linkages. These candidate regions remain unexplored in Indians, which is a high-risk population for type 2 diabetes. Hypothesizing regulatory regions to have a more important role in complex disorders, we examined association of 207 common variants in proximal promoter and untranslated regions of genes on 1q21-23 and 20q13 with type 2 diabetes in 2115 North Indians. Further, top signals were replicated in an independent group of 2085 North Indians. Variants-rs11265455-SLAMF1 (odds ratios (OR)=1.32, P=1.1 × 10(-3)), rs1062827-F11R (OR=1.36, P=1.7 × 10(-3)) and rs12565932-F11R (OR=1.35, P=1.8 × 10(-3)) were top signals for association with type 2 diabetes whereas rs1333062-ITLN1 (OR=1.28, P=3.4 × 10(-3)) showed strongest association in body mass index-stratified analysis. Replication of these four variants confirmed associations of rs11265455-SLAMF1 (OR=1.27, P=9.1 × 10(-3)) and rs1333062-ITLN1 (OR=1.25, P=1.1 × 10(-3)) with type 2 diabetes. Meta-analysis further corroborated the association of rs11265455-SLAMF1 (OR random effect=1.29, P random effect=3.9 × 10(-5)) and rs1333062-ITLN1 (OR random effect=1.19, P random effect=1.8 × 10(-4)). In conclusion, the study demonstrates that variants of SLAMF1 and ITLN1, both implicated in inflammation, are associated with type 2 diabetes in Indians.

Elevated levels of C-reactive protein as a risk factor for metabolic syndrome in Indians.

OBJECTIVE: Relationship of high sensitivity C-reactive protein (hsCRP) with metabolic syndrome (MetS) is well documented in many populations, but comprehensive data is lacking in Indian population. Thus, we set out to investigate the association of hsCRP levels with MetS and its features and the effect of obesity and insulin resistance on this association in urban Indians. METHODS: This is a cross-sectional study that included 9517 subjects comprising 4066 subjects with MetS. MetS was defined according to the modified National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) criteria for Asians. RESULTS: Median levels of hsCRP were considerably higher in individuals with MetS with higher levels in women compared to men. Among the features of MetS, waist circumference was most strongly correlated with hsCRP levels (r=0.28) and contributed maximally (ß=0.025mg/l lnhsCRP, P=7.4×10(-147)). Subjects with high risk hsCRP levels (>3mg/l) were at high risk of MetS (OR (95% CI)=1.65(1.41-1.92), P=1.7×10(-10)). Risk of MetS increased in a dose dependent manner from low risk to high risk hsCRP category with increase in BMI and HOMA-IR. CONCLUSIONS: Our findings suggest that hsCRP predicts the risk of MetS, independent of obesity and insulin resistance, and therefore, can be a valuable tool to aid the identification of individuals at risk of MetS. The study provides a lead for future investigation for effects of hsCRP, obesity, and insulin resistance on MetS in this population.

Common variants of FTO and the risk of obesity and type 2 diabetes in Indians.

Common variants of fat mass and obesity-associated gene (FTO, fat mass- and obesity-associated gene) have been shown to be associated with obesity and type 2 diabetes in population of European and non-European ethnicity. However, studies in Indian population have provided inconsistent results. Here, we examined association of eight FTO variants (rs1421085, rs8050136, rs9939609, rs9930506, rs1861867, rs9926180, rs2540769 and rs708277) with obesity and type 2 diabetes in 5364 North Indians (2474 type 2 diabetes patients and 2890 non-diabetic controls) in two stages. None of the variants including previously reported intron 1 variants (rs1421085, rs8050136, rs9939609 and rs9930506) showed body mass index (BMI)-dependent/independent association with type 2 diabetes. However, rs1421085, rs8050136 and rs9939609 were associated with obesity status and measures of obesity (BMI, waist circumference and waist-to-hip ratio) in stage 2 and combined study population. Meta-analysis of the two study population results also revealed that rs1421085, rs8050136 and rs9939609 were significantly associated with BMI both under the random- and fixed-effect models (P (random/fixed)=0.02/0.0001, 0.004/0.0006 and 0.01/0.01, respectively). In conclusion, common variants of FTO were associated with obesity, but not with type 2 diabetes in North Indian population.

Primary pioglitazone failure in Asian Indian diabetics is not related to common Pro12Ala polymorph of PPAR-gamma gene.

To determine the various factors influencing glycemic response to pioglitazone monotherapy in newly diagnosed Asian Indian T2DM patients. Thirty T2DM patients (age 53.23 +/- 8.067 yrs, M: F ratio 14:16) were treated with pioglitazone for at least 14 weeks. Relationship between its glucose lowering effect and following patient parameters was studied: BMI, W:H ratio, HOMA-R, HOMA-beta and Pro12Ala polymorph of PPAR-gamma gene. Glycemic targets could be achieved in 20 (66.67%) subjects. All the parameters were comparable among responders and non-responders at the start of therapy. All the participants were homozygous for Pro allele of Pro12Ala polymorph of PPAR-gamma gene. There was a significant positive association between glycemic response to pioglitazone and W: H ratio (beta = 0.426, P = 0.034) and HOMA-R (beta = 0.563, P = 0.008). Primary pioglitazone failure cannot be explained on the basis of body fat and its distribution, insulin resistance and secretory function and Pro12Ala polymorph of PPAR-gamma gene. Among responders central obesity and high insulin resistance were associated with better glycemic response.