Etiology, clinical characteristics and mortality among Indian patients with Addison's disease.

The etiology, presentation and mortality of patients with primary adrenal insufficiency (PAI) in developing countries may differ from economically developed nations. However, information in this regard is scanty. The aim of this study was to determine the etiology and compare the clinical characteristics and mortality in infectious and autoimmune causes of PAI in Indian patients. All eligible (n = 89) patients (ages 15-83 years) diagnosed with PAI between 2006 and 2019 were studied. Patients were followed for a median duration of 5.9 (range 0.1-15.7) years. Eighty-six subjects underwent an abdominal computerized tomography scan or ultrasonography, and adrenal biopsy was performed in 60 patients. The most frequent etiologies of PAI were adrenal histoplasmosis (AH, 45%), adrenal tuberculosis (AT, 15%), autoimmunity (AI, 25%) and primary lymphoma (6%). Forty-two percent of patients presented with an acute adrenal crisis. AH and AT could not be differentiated on the basis of clinical features, except for a greater frequency of hepatomegaly-splenomegaly and type 2 diabetes mellitus (63% vs 15%, P < 0.01) in the former. Patients with an autoimmune etiology had a higher frequency of 21-hydroxylase antibodies (41% vs 3%) and autoimmune thyroid disease (46% vs 5%) vs those with infectious etiologies. Mortality was significantly higher in AH (45%) compared with AT (8%) or AI (5%) (P = 0.001). Causes of death included adrenal crises, progressive AH and unexplained acute events occurring at home. In conclusion, infections, especially AH, were the most frequent cause of PAI in north India. Despite appropriate therapy, AH had very high mortality as compared with AT and AI.

Low Diagnostic Utility of Overnight High-Dose Dexamethasone Suppression Test in ACTH-Dependent Cushing's Syndrome.

OBJECTIVE: Overnight high-dose dexamethasone suppression test (ON-HDDST) is a simple test to localize the source of ACTH in patients with ACTH-dependent Cushing's syndrome (CS). However, previous studies have reported its varying accuracy. We studied the utility of ON-HDDST in diagnosing Cushing's disease (CD) in a series of patients with CD and ectopic ACTH syndrome (EAS). METHODS: We conducted a retrospective study of 88 patients with ACTH-dependent CS (plasma ACTH > 20.0 pg/mL), who underwent an ON-HDDST. CD and EAS were diagnosed in 68 and 20 patients, respectively. Patients were investigated using MRI of the sellar region, CT of the thorax/abdomen, Gallium-68-DOTANOC PET scan, and bilateral inferior petrosal sinus sampling as required. RESULTS: Patients with EAS had a significantly higher serum cortisol after ON-HDDST than patients with CD (median [IQR], 19.9 [12.4-31.1] µg/dL vs 9.9 [5.1-25.0] µg/dL, P <.01). A suppressed ON-HDDST (≥50% fall from baseline) was noted in 44 (65%) patients with CD and 3 (15%) patients with EAS (P <.0001). Among patients with CD, cortisol suppression >50% was noted in 35 (76%) of patients with microadenoma and 7 (44%) with macroadenoma. Among patients with EAS, ON-HDDST was suppressed in 1 of 6 patients (17%) with an occult tumor and 2 of 14 patients (14%) with a localized tumor. The ROC curve plotted for the percentage suppression of cortisol had an area under the curve (AUC) of 0.72 (P =.01). The best test parameters, with 65% sensitivity, 85% specificity, 94% positive predictive value, 42% negative predictive value, and 69% accuracy, were at 50% cutoff level. CONCLUSION: The ON-HDDST had a poor diagnostic value in differentiating CD and EAS.

Hereditary Medullary Thyroid Carcinoma: Genotype, Phenotype and Outcomes in a North Indian Cohort.

BACKGROUND: Aggressiveness of hereditary medullary thyroid carcinoma (hMTC) has been conventionally described to correlate with American Thyroid Association (ATA) risk groups based on RET mutations. Recent evidence increasingly contradicts this notion. We studied the RET genotype and its correlation with disease phenotype and survival outcomes in a cohort of hMTC patients. METHODS: In a retrospective cohort of 55 hMTC patients from 23 families treated at a north Indian tertiary care institute over 15-years, RET genotype was correlated with disease phenotype (clinical, biochemical, and pathological attributes) and outcomes in terms of biochemical cure (normalization of serum calcitonin), structural cure, overall survival (OS) and disease specific survival (DSS). RESULTS: Forty-nine patients had Multiple Endocrine Neoplasia (MEN)-type 2A syndrome, 02 had MEN-2B, and 4 had familial MTC. Two patients belonged to highest ATA risk, 41 to high-risk, and 12 to moderate risk categories. Age of the patients or stage of disease at presentation did not differ significantly between the ATA risk groups. Though the baseline serum calcitonin was significantly higher in highest risk category, the biochemical cure rates were not significantly different. At a median follow up of 48 months (Inter-quartile range 18-84, range 12-192) structural cure rates in ATA moderate and high risk groups were significantly higher than highest risk group (p = 0.04). No significant difference in OS between the three ATA groups of hMTC among the patients who underwent surgical treatment was observed (p = 0.098). CONCLUSIONS: The ATA moderate and high risk groups have better structural cure rates compared to ATA highest risk group. The biochemical cure and overall survival rates did not significantly differ between ATA risk-groups, and were impacted by the disease stage at presentation. The current ATA risk-groups do not reliably predict the outcomes in terms of biochemical cure and survival in hMTC patients.

Neonatal Diabetes Mellitus: Novel Mutations.

OBJECTIVE: To describe the spectrum of neonatal diabetes mellitus (NDM), document new mutations, and review published Indian literature on the etiology of NDM. METHODS: Retrospective analysis of the clinical and genetic profile of 12 NDM patients. RESULTS: Eight patients presented with NDM before the age of 6 mo. Three other patients, including 2 siblings presented in later part of infancy. An additional patient was diagnosed at age 5 y with the same etiology as her infant sibling. Four patients had transient diabetes [TNDM:1 each with a mutation in KCNJ11 and INS gene, 2 with ABCC8 mutation], 7 had permanent diabetes [PNDM: 2 siblings with complete glucokinase deficiency, 2 siblings with thiamine responsive megaloblastic anemia (TRMA), 1 with Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome and 2 with Wolcott Rallison syndrome, (WRS)]. Four patients had 5 novel mutations. Genetic etiology could not be established in 1 patient with features of insulin resistance. Poorly controlled blood glucose in the TRMA patient led to hyperglycemia-induced hemichorea-hemiballismus, a rare manifestation in children. CONCLUSIONS: The authors describe 5 novel mutations, in the EIF2AK3, ABCC8, and GCK genes, a homozygous mutation at the ABCC8 locus presenting as TNDM, an obscure phenotype of the GCK gene mutation, and hyperglycemia-induced hemichorea-hemiballismus in a patient with TRMA. In India, PNDM is most commonly due to WRS similar to Middle Eastern countries with high consanguinity rates.

Results of Percutaneous Computed Tomography-Guided Biopsy of Adrenal Lesions and Spectrum of Computed Tomography Findings.

OBJECTIVE: Adrenal enlargement occurs in various conditions such as infections, benign, and malignant neoplasms. Percutaneous computed tomography (CT)-guided adrenal biopsy is a safe method for obtaining tissue specimen in cases where diagnosis cannot be established on imaging and biochemical grounds. The study aims to evaluate diagnostic yield, accuracy, and complications of percutaneous CT-guided adrenal biopsies. Furthermore, CT findings of various adrenal lesions have been described. MATERIALS AND METHODS: Data of CT-guided adrenal biopsies performed from September 2009 to May 2019 were analyzed. Biopsies were performed on a 64-slice or a 128-slice multidetector CT scanner using a coaxial technique. Pathological and microbiological reports were retrieved from the hospital information system. Clinical details were obtained from clinical case records. RESULTS: CT-guided adrenal biopsies were performed in 48 patients, 37 males and 11 females. Adrenal insufficiency was present in 31 (64%) cases and bilateral adrenal glands were affected in 35 (73%). Biopsy yielded a diagnosis in 35 cases (72.9%). The final diagnosis was achieved in 43 (90%) cases. Combined accuracy of CT-guided biopsy for identifying malignancy and infection was 88.3%. Adrenal histoplasmosis (AH) was the most common entity diagnosed (44%). After combining histopathology and microbiology results, the sensitivity for diagnosing AH was 100%. One (2%) patient had a major complication in the form of intra-abdominal hemorrhage requiring transfusion. Local hematoma and mild stable pneumothorax were noted in one patient each. CONCLUSION: Percutaneous CT-guided biopsy is a safe procedure for the diagnosis of adrenal lesions. It has good accuracy for diagnosing adrenal conditions such as infections and malignancies. However, the specific diagnosis of benign adrenal lesions was difficult to make. AH, tuberculosis, and metastasis have overlapping imaging findings.

Genetic Profile of Indian Pheochromocytoma and Paraganglioma Patients - A Single Institutional Study.

BACKGROUND AND AIMS: Pheochromocytomas (PCCs) and Paragangliomas (PGL) are rare catecholamine producing tumors that may present in sporadic or familial settings. Despite vast strides in understanding of PCC/PGL genetics in the last two decades, there is a dearth of information from India. The aim here is to study the prevalence of genetic mutations in Indian PCC/PGL patients. SETTINGS AND DESIGN: Tertiary care academic hospital; prospective study. METHODS: 50 histopathologically diagnosed PCC/PGL patients formed the study group. Clinical, biochemical, pathological attributes and outcomes were documented and the phenotype was compared to the genotype. Succinyl dehydrogenase (SDH), Re-Arranged during Transfection (RET), Von-Hippel-Lindau (VHL) and NeuroFibromatosis-1 (NF1) mutations were studied. Additionally, immunohistochemisty for SDHB was also done, and the results compared to mutational analysis of SDH by MLPA (Multiplex Ligation-dependent Probe Activation). STATISTICAL ANALYSIS: Independent samples t-test and Fisher's exact test were used as appropriate. P values ≤0.05 were considered statistically significant. RESULTS: The mean age was 34.3 years. Of the 50 patients, 27 were males and 23 females. 10 patients (20%) in all were detected to have a genetic mutation. 6 patients possessed a RET mutation, while two had VHL mutations. No patient presented with a NF1 mutation. 2 patients had a SDH mutation, and Immunohistochemistry for SDHB correlated with mutational analysis for these patients. CONCLUSIONS: The proportion of patients with a familial variant of PCC/PGL is more than what the historic "Rule of Ten" suggests. Our study found that one in five patients have a genetic mutation. PCC/PGL patients with genetic mutations not only require more stringent follow-up, but also screening of family members.

Elevated FGF23 in a patient with hypophosphatemic osteomalacia associated with neurofibromatosis type 1.

CONTEXT: The mechanism behind hypophosphatemia in the setting of neurofibromatosis type 1 (NF1) is not known. We describe a possible role of fibroblast growth factor-23 (FGF23) in the pathophysiology of hypophosphatemia in a patient with NF1. CASE DESCRIPTION: A 34-year woman with NF1 presented with severe hypophosphatemia, osteomalacia, and elevated plasma FGF23. The patient had considerable improvement on replacement of oral phosphate. Two Ga68 DOTANOC PET-CT scans over a period of 2 years failed to detect any localized uptake. Immuno-staining for FGF23 was absent in the neural-derived tumour cells of the neurofibromas in the proband. CONCLUSION: The patient with NF1 had elevated circulating FGF23. Tumour cells in the neurofibroma tissues did not stain for FGF23 on IHC. It is unlikely for neurofibromas to contribute to high circulating FGF23 levels in the proband.

Novel mutations and spectrum of the disease of NR0B1 (DAX1)-related adrenal insufficiency in Indian children.

Background X-linked adrenal hypoplasia congenita (AHC), due to mutations in the nuclear receptor superfamily 0, group B, member 1 (NR0B1)/dosage-sensitive sex reversal, AHC, critical region on the X chromosome, gene 1 (DAX1) gene, usually presents with a salt-wasting adrenal crisis in infancy and hypogonadotropic hypogonadism (HH) in adolescents. Genetic reports in the literature from patients of diverse ethnicity are limited. We describe the atypical clinical characteristics and molecular genetic results in six Indian patients. Methods Both exons and flanking intronic sequences of the NR0B1 gene were amplified and sequenced in five patients. In the sixth patient, suspected to have a large deletion, multiplex ligation-dependent probe amplification (MLPA) and chromosomal microarray analysis were performed. Results Sequencing revealed three novel mutations: a nonsense mutation (c.776C > A), a deletion (c.298del), both causing loss of domains which are highly conserved among nuclear receptor families, and a missense mutation (c.1112T > C). In-silico analysis by structure-based protein modeling predicted a de-stabilizing effect of the novel missense mutation. Two previously reported mutations were seen in patients with atypical manifestations such as late-onset adrenal insufficiency and precocious puberty. One patient had a 7.15-Mb contiguous deletion involving the NR0B1, Duchenne muscular dystrophy (DMD), glycerol kinase (GK) and melanoma antigen, family B, 16 (MAGEB16) genes. Conclusions Our report emphasizes the wide clinical spectrum of AHC, including rare manifestations, and enumerates unique mutations in the NR0B1 gene.

Decreased bone mineral density in women with Sheehan's syndrome and improvement following oestrogen replacement and nutritional supplementation.

Sheehan's syndrome (SS) is an important cause of pan-hypopituitarism in women. There is scanty information on bone mineral density (BMD) in this condition. We determined BMD and the changes in BMD after oestrogen (E2) replacement and nutritional supplementation in women with SS. In a cross-sectional study, BMD was measured by DEXA in 83 patients [age (mean ± SD) 42 ± 9.2 years] and compared with an equal number of matched controls. In a sub-set of 19 patients, we conducted an open-label, prospective study to determine changes in BMD after 1 year of replacement of E2, and calcium and vitamin D3 supplementation. All patients had low serum IGF-1 and E2, while 98% had ≥ 3 pituitary hormone deficiencies. Compared with Indian reference standards, 47% had decreased bone mass (Z-score ≤ - 2.0). BMD Z-scores were decreased at all sites, being most marked in the lumbar spine and femoral neck. At the lumbar spine, BMD was lowest among the age group 21-30 years. Women with SS also had significantly lower BMD Z-scores at all three sites on comparison with ethnic controls. On multivariate analysis, BMD Z-score was associated with weight, daily calcium intake and age (lumbar spine). In the prospective study, 1 year of therapy improved BMD Z-score at lumbar spine (- 1.4 ± 1.2 vs. - 1.1 ± 1.1, p = 0.02), but not at hip or femoral neck. In conclusion, patients with SS had significantly lower BMD compared to controls at all three sites. Replacement of E2 and supplementation with calcium/vitamin D3 lead to significant improvement in lumbar spine BMD.

Concurrent extrahepatic autoimmune disorders: unexplored dimension of autoimmune liver disease in children.

BACKGROUND AND AIM: No comprehensive and prospective data are available for concurrent extrahepatic autoimmune disorders (CEAIDs) in children with autoimmune liver disease (AILD). The aim of this study was to evaluate CEAIDs in AILD and their effect on AILD outcome. PATIENTS AND METHODS: Enrolled AILD and CEAIDs children were diagnosed on the basis of simplified and standard diagnostic criteria, respectively. The clinicopathological profile, treatment response, and outcome were compared between AILD with CEAIDs (group A) and AILD without CEAIDs (group B). RESULTS: In 62 AILD children, CEAIDs were found in 42% (n=26) [vitiligo (42%), celiac disease (CD) (15%), potential CD (15%), autoimmune hemolytic anemia (AIHA) (15%)]. CEAIDs were asymptomatic in 75%. Single CEAID was found in 81% (21/26) and multiple CEAID was found in 19% (5/26). Significantly less biochemical remission (46.1 vs. 74.2%, P=0.03), more treatment failure (23 vs. 3.2%, P=0.04), and higher mortality (15.3 vs. 3.2%, P=0.04) were encountered in group A compared with group B. On multivariate analysis (n=57), less biochemical remission in vitiligo (P=0.04); more treatment failure in AIHA (P=0.004) and vitiligo (P=0.04); and high mortality in AIHA (P=0.02) subgroups were reported. CD treatment has good impact on AILD outcome. All cases of diabetes mellitus in AILD were steroid-induced rather than because of autoimmunity (absence of antibody against tyrosine phosphatase and glutamic acid decarboxylase and elevated C-peptide). CONCLUSION: All AILD children should be screened for CEAIDs as the majority are asymptomatic. The AILD outcome was favorable in CD, but poor in vitiligo and AIHA. We suggest the incorporation of CEAIDs in a pediatric AILD scoring system.

Oncogenic osteomalacia: role of Ga-68 DOTANOC PET/CT scan in identifying the culprit lesion and its management.

OBJECTIVE: The aim of this study was to evaluate the role of 68Ga-DOTANOC positron emission tomography (PET)/CT scan in localization of culprit lesion for biopsy and required intervention [surgical excision/radiofrequency ablation (RFA)] in patients with long-standing oncogenic osteomalacia (OOM)/tumour-induced osteomalacia. METHODS: 17 patients (8 males and 9 females) underwent 68Ga-DOTANOC PET/CT scan. The patients referred with clinical and biochemical evidence of hypophosphatemia and raised fibroblast growth factor-23. Qualitative and semi-quantitative parameters were used to identify culprit lesions. RESULTS: 68Ga-DOTANOC PET/CT scan revealed 52 lesions in 17 patients, and 37/52 of these lesions were tracer avid. 26/37 lesions were non-specific focal tracer-avid skeletal lesions (fractures or degenerative changes). 11/37 tracer-avid skeletal lesions present in 9 patients (3 lesions in 1 patient and 1 each in rest of the 8 patients) were highly suspicious for culprit lesions in view of high maximum standardized uptake value (SUVmax) (range 1.5-15.4; mean 7.0 ± 4.6), lesion size (0.9-5.0 cm; mean 3.3 ± 1.5) and associated soft-tissue component. During subsequent imaging with CT/MRI, 7/9 patients showed concordant lesions which were excised or biopsied and histopathologically verified as phosphaturic mesenchymal tumours. Surgical excision was resorted to in most of the detected lesions, and RFA was performed in one patient. CONCLUSION: There is some overlap in SUVmax between fracture-/bone-associated lesions and culprit lesions with a tendency of most non-culprit lesions to have lower SUVmax and no associated soft-tissue component. In such scenario, intensely tracer-avid, larger non-fracture lesions with soft-tissue component may lead to identification of culprit lesion among multiple lesions. Following detection of culprit lesion, surgical removal is the best treatment. RFA is alternative to surgery in cases where surgery is not possible owing to osteopenia/poor bone health. Advances in knowledge: The main challenge in patients of long-standing OOM is the presence of multiple skeletal lesions (both tumour- or tracer-avid fractures), and it is confusing to identify culprit lesion. This was noted in our study with 68Ga-DOTANOC and has not been mentioned in studies performed with 68Ga-DOTATATE/TOC PET/CT. In such scenario, 68Ga-DOTANOC PET/CT needs to be reviewed and read thoroughly to localize the culprit lesion out of the multiple tracer-avid lesions.

Genotype-Phenotype Correlation in Indian Patients with MEN2-Associated Pheochromocytoma and Comparison of Clinico-Pathological Attributes with Apparently Sporadic Adrenal Pheochromocytoma.

INTRODUCTION: Pheochromocytoma (PCC) manifests in up to 50% of MEN2 patients. We correlated the clinico-pathological features of MEN2-associated PCC (MEN-PCC) with RET mutations and compared them with non-MEN adrenal-PCCs. METHODS: In this retrospective single institution study on a large PCC database (n = 208, 1997-2014) 24 MEN-PCC patients with known RET mutations were reviewed. Excluding 7 with incomplete data, the study cohort of 17 MEN-PCC patients from 11 kindreds (M:F::7:10) was identified. Clinical, biochemical, pathological attributes, and outcomes in the MEN-PCC group were correlated with the genotype, and further compared with non-MEN, apparently sporadic adrenal-PCCs (n = 132, excluding 37 extra-adrenal and 15 VHL/NF1/SDH-associated PCC). RESULTS: Components of MEN2 encountered included MTC in 13(76.5%), Marfanoid habitus in 2, and PHPT, cutaneous lichen amyloidosis and mucosal neuromas in 1 patient each. In 11(64.7%), PCC was the first detected MEN2 component (Symptomatic:8, Incidentaloma:3). Four (23.5%) were normotensive; 8(47.1%) had bilateral PCC (7 synchronous, 1 metachronous). Surgery for PCC included laparoscopic adrenalectomy in 12; and cortical-sparing adrenalectomy in 2 of 8 bilateral PCC patients. Mean MEN-PCC tumor size was 6.9 ± 3.9 cm, and 6(35%) had additional adrenal medullary hyperplasia. Four different genotypes were encountered, commonest involving codon 634, others being 804 and 918. Mean age in MEN-PCC (27.7 ± 12.2 years) was lower than non-MEN PCC (39.4 ± 15.7, p = 0.018). Proportion of pediatric patients (35.3% in MEN-PCC vs. 12.9% in non-MEN-PCC, p = 0.007), bilateral tumors (47.1% in MEN-PCC, 4.5% in non-MEN-PCC, p < 0.001), and adrenal medullary hyperplasia (35.2% in MEN-PCC, 0.7% in non-MEN-PCC, p < 0.001) were different. Median 24-hour urinary metanephrines was significantly higher in index MEN-PCC patients, than non-MEN-PCC (634 vs. 214 mcg/24 h, p value = 0.006), but was non-significantly higher in non-index MEN-PCC patients. Mean tumor sizes were comparable in the two groups. None of MEN-PCC patients had malignant PCC, compared to 7(5.3%) in non-MEN-PCC. CONCLUSIONS: In this cohort of MEN-PCC from India, the commonest causative RET mutations for MEN-PCC involved codon 634. MEN-PCC patients were younger, and more frequently had bilateral PCC than non-MEN disease. MEN-PCC patients in India are diagnosed with large tumors and extremely high catecholamine/metanephrine levels.

Prevalence of Graves' ophthalmopathy in patients with Graves' disease presenting to a referral centre in north India.

BACKGROUND & OBJECTIVES: The prevalence of Graves' ophthalmopathy (GO) varies widely in different ethnic groups. Indians have been reported to have a lower prevalence of Graves' ophthalmopathy as compared to Caucasians of European origin, but data are sparse and inconclusive. We studied the prevalence, clinical features and association of GO in Indian patients with Graves' disease attending a referral centre in north India. METHODS: A prospective study was conducted on 235 consecutive newly referred north Indian patients with Graves' disease presenting to a tertiary care centre in north India. All patients underwent a comprehensive ophthalmological examination as per the European Group on Graves' Orbitopathy (EUGOGO) recommendations. RESULTS: GO was diagnosed in 65 patients (prevalence 28%; 95% confidence interval 22-33%). The prevalence was similar in males (28%) and females (27%). It was mild in 83 per cent, moderate-severe in 15 per cent and sight-threatening in only 2 per cent of cases. Ophthalmopathy was clinically active in only two (3%) cases. Upper eyelid retraction was the most common manifestation (83%), followed by exophthalmos (75%). Extra-ocular muscle involvement (5%) and optic nerve dysfunction (2%) were uncommon. The risk of GO was 3.9- fold (95% confidence interval 1.1-13.6) higher in smokers compared to non-smokers. However, severity of disease in smokers was similar to non-smokers. On multivariate logistic regression analysis, GO was associated only with high thyrotropin receptor antibody titres and current smoking. INTERPRETATION & CONCLUSIONS: Among north Indian patients with GD studied at a referral center, the prevalence of GO was similar to Caucasians of European descent, but clinically active and severe ophthalmopathy was uncommon. More studies are needed to confirm these findings.

Prospective study to compare peri-operative hemodynamic alterations following preparation for pheochromocytoma surgery by phenoxybenzamine or prazosin.

BACKGROUND: Prospective studies comparing the efficacy of selective versus nonselective alpha blockers for preoperative preparation of pheochromocytoma (PCC) are lacking. In this prospective nonrandomized study, we compared the outcome of preoperative preparation with phenoxybenzamine (PBZ) and prazosin (PRZ) in terms of perioperative hemodynamic alterations. METHODS: The study was conducted at a tertiary referral center from July 2010 to December 2012. Thirty-two patients with PCC underwent operation after adequate preparation with PBZ (n = 15) or PRZ (n = 17). Five pediatric and adolescent patients were excluded because of different hemodynamics in this population. Perioperative monitoring was done for pulse rate (PR) and blood pressure(BP) alterations, occurrence of arrhythmias, and time taken to achieve hemodynamic stability. Groups were compared with the Mann-Whitney test, Student's t test, and the χ2 test as applicable. RESULTS: Patients in the two groups were similar in age,gender, 24 h urinary metanephrine and normetanephrine levels, and type of procedure. Patients prepared with PRZ had significantly more intraoperative episodes of transient hypertension (systolic BP ≥ 160 mmHg) and hypertensive urgency (BP >180/110 mmHg) (p 0.02, 0.03, respectively). More patients receiving PRZ suffered from transient severe hypertension (SBP ≥ 220 mmHg) (p 0.03). The PRZ group also had more median maximum SBP (233 mmHg vs PBZ 181.5 mmHg) (p = 0.01) and lesser median minimum SBP (71 mmHg vs PBZ 78 mmHg) (p 0.03). No significant differences were found between the study groups for changes in PR, postoperative BP alterations,occurrence of arrhythmias, and time taken to achieve hemodynamic stability. CONCLUSIONS: PBZ was found superior to PRZ in having fewer intraoperative hemodynamic fluctuations.

Wilm's tumor-1 protein levels in urinary exosomes from diabetic patients with or without proteinuria.

BACKGROUND: Podocyte injury is an early feature of diabetic nephropathy (DN). Recently, urinary exosomal Wilm's tumor-1 protein (WT1), shed by renal epithelial cells, has been proposed as a novel biomarker for podocyte injury. However, its usefulness as biomarker for early diabetic nephropathy has not been verified yet. We investigated urinary exosomal WT1 in type-1 diabetic patients to confirm its role as a non-invasive biomarker for predicting early renal function decline. METHODS: The expression of WT1 protein in urinary exosomes from spot urine samples of type-1 diabetes mellitus patients (n = 48) and healthy controls (n = 25) were analyzed. Patients were divided based on their urinary albumin excretion, ACR (mg/g creatinine) into non- proteinuria group (ACR<30 mg/g, n = 30) and proteinuria group (ACR>30 mg/g, n = 18). Regression analysis was used to assess the association between urinary exosomal levels of WT1 with parameters for renal function. Receiver Operating Characteristic (ROC) curve analysis was used to determine the diagnostic performance of exosomal WT-1. RESULTS: WT1 protein was detected in 33 out of 48 diabetic patients and in only 1 healthy control. The levels of urinary exosomal WT1 protein is significantly higher (p = 0.001) in patients with proteinuria than in those without proteinuria. In addition, all the patients with proteinuria but only half of the patients without proteinuria were positive for exosomal WT1. We found that the level of exosomal WT1 were associated with a significant increase in urine protein-to-creatinine ratio, albumin-to-creatinine ratio, and serum creatinine as well as a decline in eGFR. Furthermore, patients exhibiting WT1-positive urinary exosomes had decreased renal function compared to WT1-negative patients. ROC analysis shows that WT-1 effectively predict GFR<60 ml. min-1/1.73 m(2). CONCLUSION: The predominant presence of WT1 protein in urinary exosomes of diabetic patients and increase in its expression level with decline in renal function suggest that it could be useful as early non-invasive marker for diabetic nephropathy.

Double blind randomized control study of intramuscular vitamin D3 supplementation in tropical calcific pancreatitis.

Vitamin D deficiency is prevalent in chronic pancreatitis (CP), but the optimal route and dose of vitamin D supplementation are unknown. We evaluated the relative efficacy of two different doses of intramuscular (i.m.) vitamin D(3) in patients with CP and vitamin D insufficiency. In a double-blind randomized study, 40 patients with tropical calcific pancreatitis with serum 25-hydroxyvitamin D (25OHD) <75 nmol/L (mean 27.0 ± 14.5 nmol/L, <50 nmol/L in 90 %) were divided into three groups. Groups 1 and 2 received 600,000 IU (15,000 µg) and 300,000 IU (7,500 µg) i.m. cholecalciferol, respectively, while group 3 received i.m. saline. All groups received 1 g calcium and 500 IU (12.5 µg) vitamin D(3) orally daily and were studied for 9 months. The primary outcome was the proportion of patients with vitamin D sufficiency (25OHD >75 nmol/L) at 6 months. Vitamin D sufficiency was significantly different in the three groups (85, 29, and 0 % in groups 1, 2, and 3, respectively; p < 0.001). Mean 25OHD remained >75 nmol/L in months 1-6 in group 1 but reached a lower level (50-75 nmol/L) at these time points in group 2. At 6 months, serum alkaline phosphatase decreased significantly only in group 1 (230 ± 73 vs 165 ± 39 IU/L, p = 0.004). No patient in any group developed hypervitaminosis D or hypercalcemia. In conclusion, in patients with CP, a single i.m. injection of 600,000 IU was more effective at achieving vitamin D sufficiency over 6 months compared with 300,000 IU vitamin D(3). (Clinical Trials.gov number NCT00956839).

Intensive glycaemic control in type 2 diabetes mellitus: does it improve cardiovascular outcomes?

With growing urbanization and economic development, there is a rapid increase in the incidence of type 2 diabetes mellitus (T2DM) in India. T2DM is associated with 2-4 times higher risk for cardiovascular disease (CVD), including coronary artery disease, stroke and peripheral vascular disease. Several studies have shown the benefit of intensive glycaemic control in reducing the frequency of diabetic microvascular complications such as retinopathy and nephropathy. Results of long term follow up of patients with diabetes, who were enrolled in earlier trials, have shown that initial intensive glycaemic control led to a reduction in CVD outcomes when compared with standard therapy. However, it is unclear if intensive glycaemic control, aiming to reduce haemoglobin A1c to levels even lower than the current goal of <7%, will similarly lead to reduction in the rates of CVD. Recently, the results of 3 large, randomized controlled trials have been published, which suggest that in established T2DM with previous CVD or high risk of CVD, the benefits of intensive glycaemic control when compared with conventional good control, are minimal with regards to reduction of cardiovascular outcomes. Intensive therapy increases the risk of side-effects such as severe hypoglycaemia and weight gain. The implementation of such a therapy, with rigorous attention to frequent monitoring of blood glucose and visits to the physician, is not likely to be possible on a large scale, especially in a developing country such as India. The aim of management of patients with established T2DM should be to achieve the goal of good glycaemic control (haemoglobin A1c<7%), with avoidance of hypoglycaemia. It is equally, if not more important, to control other risk factors of CVD by paying greater attention to lifestyle measures (weight loss if overweight or obese, regular exercise, cessation of smoking), rigorous control of blood pressure (<130/80 mmHg) and low density lipoprotein (LDL) cholesterol (<100 mg/dl or <70 mg/dl if already diagnosed with CVD) and the prophylactic use of low dose aspirin as per current recommendations. A multifactorial approach targeting multiple cardiovascular risk factors is likely to be most effective in reducing CVD outcomes in T2DM.

High prevalence of low bone mineral density in patients with tropical calcific pancreatitis.

OBJECTIVES: Patients with tropical calcific pancreatitis (TCP) have multiple risk factors for developing low bone mineral density (BMD). We studied BMD and serum 25-hydroxyvitamin D (25[OH]D) in north Indian TCP patients. METHODS: In a cross-sectional study, 72 TCP patients (mean age, 31 ± 10 years) and 100 controls were studied. Serum 25(OH)D was measured in all subjects; BMD was measured by dual-energy x-ray absorptiometry in 56 adult patients and 4 children and compared with a reference Indian population. RESULTS: Mean BMD and BMD Z-scores at the lumbar spine and total hip were significantly lower in all age groups. The BMD Z-scores at the lumbar spine and total hip were -1.0 ± 1.0 and -1.2 ± 1.2, respectively. Low bone density (Z-score ≤ -2 at ≥ 1 sites) was present in 22 (39%) adult patients and 3 of the 4 children studied. On multivariate analysis, BMD Z-scores were positively associated with body mass index and inversely with pancreatitis. Vitamin D deficiency (25[OH]D < 50 nmol/L) was equally prevalent in patients (86%) and controls (85%). CONCLUSIONS: Despite their young age, patients with TCP have significantly low BMD. Measures to improve nutrition should be instituted in all TCP patients from an early age.