Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study).

BACKGROUND: Vitamin D has an immunomodulatory role but the effect of therapeutic vitamin D supplementation in SARS-CoV-2 infection is not known. AIM: Effect of high dose, oral cholecalciferol supplementation on SARS-CoV-2 viral clearance. DESIGN: Randomised, placebo-controlled. PARTICIPANTS: Asymptomatic or mildly symptomatic SARS-CoV-2 RNA positive vitamin D deficient (25(OH)D<20 ng/ml) individuals. INTERVENTION: Participants were randomised to receive daily 60 000 IU of cholecalciferol (oral nano-liquid droplets) for 7 days with therapeutic target 25(OH)D>50 ng/ml (intervention group) or placebo (control group). Patients requiring invasive ventilation or with significant comorbidities were excluded. 25(OH)D levels were assessed at day 7, and cholecalciferol supplementation was continued for those with 25(OH)D <50 ng/ml in the intervention arm. SARS-CoV-2 RNA and inflammatory markers fibrinogen, D-dimer, procalcitonin and (CRP), ferritin were measured periodically. OUTCOME MEASURE: Proportion of patients with SARS-CoV-2 RNA negative before day-21 and change in inflammatory markers. RESULTS: Forty SARS-CoV-2 RNA positive individuals were randomised to intervention (n=16) or control (n=24) group. Baseline serum 25(OH)D was 8.6 (7.1 to 13.1) and 9.54 (8.1 to 12.5) ng/ml (p=0.730), in the intervention and control group, respectively. 10 out of 16 patients could achieve 25(OH)D>50 ng/ml by day-7 and another two by day-14 [day-14 25(OH)D levels 51.7 (48.9 to 59.5) ng/ml and 15.2 (12.7 to 19.5) ng/ml (p<0.001) in intervention and control group, respectively]. 10 (62.5%) participants in the intervention group and 5 (20.8%) participants in the control arm (p<0.018) became SARS-CoV-2 RNA negative. Fibrinogen levels significantly decreased with cholecalciferol supplementation (intergroup difference 0.70 ng/ml; P=0.007) unlike other inflammatory biomarkers. CONCLUSION: Greater proportion of vitamin D-deficient individuals with SARS-CoV-2 infection turned SARS-CoV-2 RNA negative with a significant decrease in fibrinogen on high-dose cholecalciferol supplementation. TRIAL REGISTER NUMBER: NCT04459247.

Triple A (Allgrove) syndrome due to AAAS gene mutation with a rare association of amyotrophy.

INTRODUCTION: Triple A (Allgrove) syndrome is a rare autosomal recessive disorder characterized by cardinal features of primary adrenal insufficiency (AI) due to adrenocorticotropic hormone (ACTH) resistance, achalasia, and alacrima. It is frequently associated with neurological manifestations such as autonomic dysfunction, cognitive dysfunction, cranial nerve, or motor involvement. Amyotrophy/motor neuron disease is a rare association. CASE PRESENTATION: We herein report a 19-year-old boy diagnosed with triple A syndrome (TAS), with the classic triad of ACTH-resistant adrenal insufficiency, achalasia, and alacrima. Additionally, he had distal spinal muscle amyotrophy. Alacrima was the earliest feature evident in early childhood, followed by achalasia at 12 years of age. He was diagnosed with AI at the age of 19 years, with involvement of the mineralocorticoid axis. Further evaluation showed a neurogenic pattern on electromyography, consistent with a diagnosis of motor neuron disease. A nerve conduction study revealed no significant neuropathy. Genetic analysis confirmed a pathogenic homozygous mutation in the AAAS gene c.43C>A, p.Gln15Lys. He improved with glucocorticoid and mineralocorticoid supplements for AI, and nifedipine for achalasia and artificial tears. He is planned for esophagomyotomy. CONCLUSION: In any young patient with AI not due to congenital adrenal hyperplasia, Allgrove syndrome should be ruled out. Though mineralocorticoid sparing pattern is classical, it can rarely be involved, as seen in the index case. Various components of the syndrome, as well as amyotrophy and other neurologic features, may present in a metachronous fashion. Hence, a high index of clinical suspicion can aid in early diagnosis and management.

Vitamin D supplementation improves simvastatin-mediated decline in exercise performance: A randomized double-blind placebo-controlled study.

BACKGROUND: The aim of the present study was to determine the effect of vitamin D supplementation on simvastatin-mediated changes in cardiorespiratory fitness and skeletal muscle mitochondrial content after exercise in adults with type 2 diabetes mellitus (T2DM). METHODS: Vitamin D-deficient T2DM patients aged 25-50 years performed moderate intensity aerobic exercise for 12 weeks and were randomized to receive simvastatin 40 mg daily, simvastatin 40 mg daily plus vitamin D 60 000 units once weekly, or vitamin D 60 000 units once weekly. The primary outcomes were cardiorespiratory fitness (peak oxygen consumption) and skeletal muscle mitochondrial content (citrate synthase activity in the vastus lateralis) following simvastatin and/or vitamin D replacement therapy. RESULTS: Twenty-eight patients completed the study. Cardiorespiratory fitness decreased by 8.4% (P < 0.05) following 12 weeks of simvastatin therapy. Vitamin D supplementation blunted the decline in cardiorespiratory fitness to 0.6% (P < 0.05 for between-group difference in change from baseline). Similarly, skeletal muscle mitochondrial content decreased by 3.6% with simvastatin, but improved by 12.1% on supplementation with vitamin D, although the between-group difference was not significant. Vitamin D alone increased cardiorespiratory fitness and mitochondrial content by 7.1% (P < 0.05) and 16.7%, respectively. CONCLUSIONS: Simvastatin tends to cause deterioration in exercise-associated cardiorespiratory fitness and skeletal muscle mitochondrial content in adults with T2DM, which is blunted by vitamin D supplementation.

The microbiology of diabetic foot infections in patients recently treated with antibiotic therapy: A prospective study from India.

AIM: Clinicians often treat clinically infected diabetic foot ulcers without information from cultures of the wound. The results of wound cultures may also be affected by previous antibiotic therapy. Thus, we aimed to study the microbial isolates, and antimicrobial sensitivity of previously treated patients with a clinically infected DFU. RESEARCH DESIGN AND METHODS: 293 consecutive patients with clinically infected DFU on prior antimicrobial treatment within the immediate past few days for a duration greater than one week were evaluated for microbial etiology, antibiotic sensitivity and final outcomes. Appropriate tissue samples i.e. purulent drainage, soft-tissue and/ or bone were obtained for aerobic/anaerobic cultures and antimicrobial sensitivities. 71 patients with missing prior antibiotic data were excluded. RESULTS: 313 tissue samples obtained from 222 patients isolated 317 causative organisms. Most of the culture results from tissue specimens were mono-microbial (93.2%) compared to 37% in our previous cohort of 60 patients. Pseudomonas aeruginosa was the most common organism isolated on culture of bone (26.9%) or soft tissue (23.2%) specimen, respectively. Only 23% and 64% of P. aeruginosa isolates and 5.6% and 44% of Acinetobacter sp. were sensitive to quinolones and cephalosporins, respectively. CONCLUSIONS: Clinically infected DFU recently treated with antibiotics have predominant monomicrobial and multi drug-resistant infection. Quinolones as an empirical antibiotic choice may not be appropriate in this setting.

Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians.

BACKGROUND: To explore underlying molecular mechanisms in the pathogenesis of symptomatic sporadic primary hyperparathyroidism (PHPT). MATERIALS AND METHODS: Forty-one parathyroid adenomas from patients with symptomatic PHPT and ten normal parathyroid glands either from patients with PHPT (n=3) or from euthyroid patients without PHPT during thyroid surgery (n=7) were analyzed for vitamin D receptor (VDR), calcium-sensing receptor (CASR), cyclin D1 (CD1), and parathyroid hormone (PTH) expressions. The protein expressions were assessed semiquantitatively by immunohistochemistry, based on percentage of positive cells and staining intensity, and confirmed by quantitative real-time PCR. RESULTS: Immunohistochemistry revealed significant reductions in VDR (both nuclear and cytoplasmic) and CASR expressions and significant increases in CD1 and PTH expressions in adenomatous compared with normal parathyroid tissue. Consistent with immunohistochemistry findings, both VDR and CASR mRNAs were reduced by 0.36- and 0.45-fold change (P<0.001) and CD1 and PTH mRNAs were increased by 9.4- and 17.4-fold change respectively (P<0.001) in adenomatous parathyroid tissue. PTH mRNA correlated with plasma PTH (r=0.864; P<0.001), but not with adenoma weight, while CD1 mRNA correlated with adenoma weight (r=0.715; P<0.001). There were no correlations between VDR and CASR mRNA levels and serum Ca, plasma intact PTH, or 25-hydroxyvitamin D levels. In addition, there was no relationship between the decreases in VDR and CASR mRNA expressions and the increases in PTH and CD1 mRNA expressions. CONCLUSIONS: The expression of both VDR and CASR are reduced in symptomatic PHPT in Asian Indians. In addition, CD1 expression was greatly increased and correlated with adenoma weight, implying a potential role for CD1 in adenoma growth and differential clinical expression of PHPT.

Celiac disease: A missed cause of metabolic bone disease.

INTRODUCTION: Celiac disease (CD) is a highly prevalent autoimmune disease. The symptoms of CD are varied and atypical, with many patients having no gastrointestinal symptoms. Metabolic bone disease (MBD) is a less recognized manifestation of CD associated with spectrum of musculoskeletal signs and symptoms, viz. bone pains, proximal muscle weakness, osteopenia, osteoporosis, and fracture. We here report five patients who presented with severe MBD as the only manifestation of CD. MATERIALS AND METHODS: Records of 825 patients of CD diagnosed during 2002-2010 were retrospectively analyzed for clinical features, risk factors, signs, biochemical, and radiological parameters. RESULTS: We were able to identify five patients (0.6%) of CD who had monosymptomatic presentation with musculoskeletal symptoms and signs in the form of bone pains, proximal myopathy, and fragility fractures without any gastrointestinal manifestation. All the five patients had severe MBD in the form of osteopenia, osteoporosis, and fragility fractures. Four of the five patients had additional risk factors such as antiepileptic drugs, chronic alcohol consumption, malnutrition, and associated vitamin D deficiency which might have contributed to the severity of MBD. CONCLUSION: Severe metabolic disease as the only presentation of CD is rare. Patients show significant improvement in clinical, biochemical, and radiological parameters with gluten-free diet, calcium, and vitamin D supplementation. CD should be looked for routinely in patients presenting with unexplained MBD.

Prevalence and predictors of abnormal bone mineral metabolism in recently diagnosed adult celiac patients.

BACKGROUND AND AIMS: This study aimed to evaluate the prevalence of low bone mineral density (BMD) in recently diagnosed adult celiac patients and to identify the factors associated with this. METHODS: We investigated 54 newly diagnosed adult celiac patients between February 2008 and April 2009. BMD was measured in all patients and its correlation with clinical and biochemical parameters was analyzed. RESULTS: Fifty-four (24 male) newly diagnosed celiac patients with a mean±SD age of 30.6 ± 9.3 years (range 18-50) were included. Thirty-nine (72.2 %) presented with intestinal symptoms, and the rest with extraintestinal symptoms. Low vitamin D levels were seen in 11 (20.3 %) patients and elevated iPTH (secondary hyperparathyroidism) in 12 (22.2 %) patients. Twenty-one (39 %) patients had normal BMD, 23 (43 %) had osteopenia (T-score -1 to -2.5), and 10 (18 %) patients had osteoporosis (T-score <-2.5). A statistically significant association was seen between BMD and age of onset, duration of illness, serum tTGA levels, serum vitamin D levels, and histopathological changes. CONCLUSIONS: Low BMD is common in newly diagnosed adult celiac patients with approximately one fifth of them having osteoporosis. BMD should be measured in all newly diagnosed celiac patients and calcium and vitamin D supplementation included in the treatment regimen.

Microbial profile and utility of soft tissue, pus, and bone cultures in diagnosing diabetic foot infections.

OBJECTIVE: This study assessed the utility of pus, soft tissue, and bone specimens in diagnosing diabetic foot infections and the spectrum of the microbial flora and in vitro susceptibility to antibiotics. SUBJECTS AND METHODS: This prospective study was carried out in 60 consecutive patients with diabetes having clinically infected foot ulcers. Detailed history, physical examination, and investigation were carried out to diagnose the presence of osteomyelitis and the microbial etiology of foot ulcers. Foot ulcers were classified as per Wagner's classification. Soft tissue, pus, and bone samples were obtained and cultured for aerobic and anaerobic bacteria, and antimicrobial susceptibility testing was carried out as per the standard protocol. RESULTS: Causative bacteria were isolated in 55 of 60 patients, and 157 isolates were cultured from 117 specimens with an average of 1.34 isolates per cases; however, the number of isolates per specimen did not differ among the various types of samples (P=0.78). Pus and soft tissue had predominantly polymicrobial flora, whereas bone infections were monomicrobial. The isolates from soft tissue specimens were different from those from bone and pus in 57% and 54% of cases, respectively. The common bacterial isolates from 117 specimens included Escherichia coli (21%) and Proteus species (15.9%). Nearly 70% of Staphylococcus aureus isolates were methicillin sensitive. All S. aureus and Enterococcus isolates were sensitive to vancomycin. Susceptibility of Gram-negative organisms to ciprofloxacin was 50%. CONCLUSIONS: Diabetic foot infections are mostly polymicrobial with Gram-negative predominance. Multiple sampling from superficial and deep tissues, including bone, when involved, yields more relevant information diagnostically and therapeutically.

Lipid-lowering drug atorvastatin as an adjunct in the management of diabetic macular edema.

PURPOSE: To determine the efficacy of the lipid-lowering drug atorvastatin in reducing retinal hard exudates and subfoveal lipid migration after focal/grid laser photocoagulation in clinically significant macular edema in patients with diabetes with elevated serum lipids. DESIGN: Randomized case trial. METHODS: Thirty patients with type 2 diabetes with clinically significant macular edema, dyslipidemia, and hard exudates of grade 4 and above were assessed in an institutional setting. All patients were subjected to strict metabolic control within 4 to 6 weeks of enrollment. In addition, 15 patients in group A received atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor; 15 members of group B did not receive any lipid-lowering therapy. All received laser photocoagulation after a metabolic control period and were followed up for a minimum of 18 weeks. The outcome measures were reduction in hard exudates, subfoveal lipid migration, status of macular edema, and visual acuity. RESULTS: The study included 21 men and nine women with noninsulin-dependent diabetes mellitus who could achieve good metabolic control within 4 to 6 weeks of inclusion in the study. All patients had elevated serum lipids at baseline. Ten (66.6%) of 15 patients in treatment group A and two (13.3%) of 15 patients in control group B showed reduction in hard exudates (P =.007). None of the patients in group A and five (33.3%) of 15 in group B showed subfoveal lipid migration after laser photocoagulation (P =.04). Regression of macular edema was seen in nine eyes in group A and five in group B (P =.27). None of the eyes in group A and three eyes in group B showed worsening of visual acuity (P =.22). CONCLUSION: Oral atorvastatin therapy in patients with type 2 diabetes with dyslipidemia reduces the severity of hard exudates and subfoveal lipid migration in clinically significant macular edema and could be an important adjunct in the management of clinically significant macular edema.

Hypophosphatemic rickets and osteomalacia in polyostotic fibrous dysplasia.

A 17 year-old girl with polyostotic fibrous dysplasia and hypophosphatemia had inappropriately low tubular reabsorption of phosphate. She had radiological evidence of rickets and osteomalacia. The patient showed clinical improvement after treatment with phosphate supplementation, active vitamin D (calcitriol) and alendronate. It is postulated that either a phosphaturic substance elaborated from the dysplastic bone or target-organ (kidney) unresponsiveness may interfere with phosphate reabsorption in the renal tubule.