Correlation between estradiol-to-testosterone ratio and thyroid peroxidase antibody positivity in men with treatment-naïve primary hypothyroidism or euthyroidism.

Objective: Thyroid diseases pose a substantial socioeconomic burden globally. The aim of this study was to evaluate the correlation between estradiol-to-testosterone (E2/T) ratio and thyroid peroxidase antibody (TPOAb) positivity in male patients with hypothyroidism or euthyroidism. Subjects and methods: Cross-sectional observational study including 115 male patients with hypothyroidism or euthyroidism. The patients were divided into two groups based on positive or negative TPOAb results, with TPOAb positivity defined by a serum TPOAb value ≥ 35 IU/mL. Results: Patients with positive TPOAbs, compared with those with negative TPOAbs, had a higher prevalence of goiter and obesity and higher levels of total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol. The median estradiol level was higher, and the median total testosterone and sex-hormone binding globulin (SHBG) levels were lower in the TPOAb-positive versus the TPOAb-negative group (p < 0.001). In subgroup analysis including only patients with hypothyroidism (n = 80), the median E2/T ratio was higher in the TPOAb-positive group (p = 0.016). The prevalence of TPOAb positivity increased with the increase in E2/T ratio quartiles, from 37.9% in the lowest quartile to 96.2% in the highest quartile (p value for trend across all quartiles < 0.001). On adjusted multivariate analysis, the E2/T ratio emerged as an independent predictor of TPOAb positivity. An E2/T ratio cutoff value of 6.565 x10-3 demonstrated the best diagnostic accuracy, with a sensitivity of 78.2% and specificity of 67.6%. Conclusion: The present study provides insights into the role of the E2/T ratio as a predictor of thyroid disorders.

Successful management of refractory Cushing's disease with severe hypercortisolemia using etomidate and temozolomide in post-surgical failure.

Corticotropinomas account for 20% of all aggressive pituitary tumors and pituitary carcinomas and are associated with high mortality. These tumors not only cause neurovascular compromise but can also be fatal due to severe hypercortisolemia itself. Although surgery is considered the primary treatment modality, it is often partially successful or unsuccessful. Moreover, these tumors frequently recur and may be resistant to conventional treatments, including surgery and radiotherapy. Therefore, early multimodal treatment and regular follow-up are necessary. We present a case of aggressive Cushing's disease managed with combined temozolomide therapy and radiotherapy following an unsuccessful transsphenoidal surgery, resulting in significant long-term radiological and biochemical remission. In addition, etomidate infusion was administered to achieve rapid cortisol reduction, highlighting its role as a bridging therapy to other modalities in treating life-threatening and severe hypercortisolemia outside an intensive care setting.

Analysis of Drying Front Propagation and Coupled Heat and Mass Transfer During Evaporation From Additively Manufactured Porous Structures Under a Solar Flux.

Drying front propagation and coupled heat and mass transfer analysis from porous media is critical for soil-water dynamics, electronics cooling, and evaporative drying. In this study, de-ionized water was evaporated from three 3D printed porous structures (with 0.41 mm, 0.41 mm, and 0.16 mm effective radii, respectively) created out of acrylonitrile butadiene styrene (ABS) plastic using stereolithography technology. The structures were immersed in water until all the pores were invaded and then placed on the top of a sensitive scale to record evaporative mass loss. A 1000 W/m2 heat flux was applied with a solar simulator to the top of each structure to accelerate evaporation. The evaporative mass losses were recorded at 15 min time intervals and plotted against time to compare evaporation rates from the three structures. The evaporation phenomena were captured with a high-speed camera from the side of the structures to observe the drying front propagation during evaporation, and a high-resolution thermal camera was used to capture images to visualize the thermal gradients during evaporation. The 3D-structure with the smallest effective pore radius (i.e., 0.16 mm) experienced the sharpest decrease in the mass loss as the water evaporated from 0.8 g to 0.1 g within 180 min. The designed pore structures influenced hydraulic linkages, and therefore, evaporation processes. A coupled heat-and-mass-transfer model modeled constant rate evaporation, and the falling rate period was modeled through the normalized evaporation rate.

Experimental evidence that network topology can accelerate the spread of beneficial mutations.

Whether and how the spatial arrangement of a population influences adaptive evolution has puzzled evolutionary biologists. Theoretical models make conflicting predictions about the probability that a beneficial mutation will become fixed in a population for certain topologies like stars, in which "leaf" populations are connected through a central "hub." To date, these predictions have not been evaluated under realistic experimental conditions. Here, we test the prediction that topology can change the dynamics of fixation both in vitro and in silico by tracking the frequency of a beneficial mutant under positive selection as it spreads through networks of different topologies. Our results provide empirical support that meta-population topology can increase the likelihood that a beneficial mutation spreads, broaden the conditions under which this phenomenon is thought to occur, and points the way toward using network topology to amplify the effects of weakly favored mutations under directed evolution in industrial applications.

Marked increase in bone mineral density with oral phosphate and calcitriol in tumour-induced osteomalacia.

Patients with osteomalacia have a low bone mineral density (BMD) and are often misdiagnosed as osteoporosis. A marked increase in BMD is noticed following successful treatment of osteomalacia. The biochemical hallmark of tumour-induced osteomalacia (TIO) is hypophosphatemia. Patients with TIO often have severe hypophosphatemic osteomalacia and dual-energy X-ray absorptiometry may demonstrate low BMD. Surgical removal of the phosphatonin-secreting lesion restores serum phosphate, corrects osteomalacia and is associated with a dramatic increase in BMD. We report two patients with TIO and low BMD, who were treated with oral phosphate and calcitriol supplementation. The percentage increase in BMD at 33 months was as high as 94.3% in areas with the lowest BMD at baseline. The BMD at 33 months was higher than the +2SD of the population-specific reference ranges, a finding not reported in surgically treated patients with TIO. An intermittent rise in parathyroid hormone following oral phosphate supplementation might have resulted in such findings.

Rickets in proximal renal tubular acidosis: a case series of six distinct etiologies.

OBJECTIVES: Proximal renal tubular acidosis (pRTA) is characterized by a defect in the ability of the proximal convoluted tubule to reabsorb bicarbonate. The biochemical hallmark of pRTA is hyperchloremic metabolic acidosis with a normal anion gap, accompanied by appropriate acidification of the urine (simultaneous urine pH <5.3). Isolated defects in bicarbonate transport are rare, and pRTA is more often associated with Fanconi syndrome (FS), which is characterized by urinary loss of phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins, and bicarbonate. Children with pRTA may present with rickets, but pRTA is often overlooked as an underlying cause of this condition. CASE PRESENTATION: We report six children with rickets and short stature due to pRTA. One case was idiopathic, while the remaining five had a specific underlying condition: Fanconi-Bickel syndrome, Dent's disease, nephropathic cystinosis, type 1 tyrosinemia, and sodium-bicarbonate cotransporter 1-A (NBC1-A) defect. CONCLUSIONS: Five of these six children had features of FS, while the one with NBC1-A defect had isolated pRTA.

Effect of morning versus night-time administration of proton pump inhibitor (pantoprazole) on thyroid function test in levothyroxine-treated primary hypothyroidism: a prospective cross-over study.

BACKGROUND: One of the common causes of suboptimal control of thyroid stimulating hormone (TSH) in levothyroxine-treated hypothyroidism is coadministration of proton pump inhibitors (PPIs). Morning administration of pantoprazole has been shown to suppress intragastric pH to a greater extent. We therefore aimed to determine the effect of pantoprazole at different time points of the day on thyroid function test (TFT) in levothyroxine-treated overt primary hypothyroidism. METHODS: In this single centre, hospital based, prospective, two arm cross-over study (AB, BA), participants were randomized into 2 groups based on morning (6:00 am - 7:00 am simultaneously with the scheduled levothyroxine tablet) (group M) and evening (30 min before dinner) intake of 40 mg pantoprazole tablet (group N). After the initial 6 weeks (period 1), a washout period of 1 week for pantoprazole was given, and then both the groups crossed over for another 6 weeks (period 2). Patients were instructed to continue the same brand of levothyroxine tablet at empty stomach 1-hour before breakfast. Serum TSH was measured at baseline, week 6, and week 13. RESULTS: Data from 30 patients, who completed the study with 100% compliance, were analysed. Mean TSH values of the study participants were significantly higher both at week 6 and week 13 compared to the baseline. Mean baseline serum TSH concentrations for groups M and N were 2.70 (± 1.36), and 2.20 (± 1.06) µlU/mL, respectively. Mean serum TSH concentrations at the end periods 1 and 2 for group M were 3.78 (± 4.29), and 3.76 (± 2.77) while the levels in group N were 3.30 (± 1.90), and 4.53 (± 4.590) µlU/mL, respectively. There was a significant rise in serum TSH concentration across periods 1 and 2 in both the groups (F2, 58 = 3.87, p = 0.03). Within group changes in TSH across periods 1 and 2 were not statistically significant. Similarly difference in TSH between the groups, either at 6 weeks or at 13 weeks, were also not statistically significant. CONCLUSIONS: Concomitant use of pantoprazole, even for 6 weeks, leads to significant elevation in serum TSH in levothyroxine-treated patients who are biochemically euthyroid, irrespective of timing of pantoprazole intake. Early morning and night-time administration of pantoprazole have similar effect on TFT in these patients.

Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.

OBJECTIVES: 46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. CONTENT: The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. SUMMARY: The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. OUTLOOK: The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases.

Hypoplastic amelogenesis imperfecta, bilateral nephrolithiasis and FGF-23-mediated hypophosphataemia: a triad of FAM20A-related enamel renal syndrome.

Enamel renal syndrome (ERS) due to loss of function (LOF) mutation of FAM20A gene typically consists of hypoplastic amelogenesis imperfecta (AI) and bilateral nephrolithiasis/nephrocalcinosis. Recent evidence suggests that FAM20A interacts with FAM20C and increases its activity; thus LOF mutation of FAM20A leads to impaired FAM20C action. FAM20C, a golgi casein kinase, phosphorylates fibroblast growth factor (FGF)-23, prevents its glycosylation and makes it more susceptible to degradation by furine proteases. Consequently, inactivating mutations of FAM20C lead to increased concentration of bioactive and intact FGF-23 in circulation and resultant hypophosphataemia. LOF mutation of FAM20A, thus, might also be associated with FGF-23-mediated hypophosphataemia; however, such an association has never been reported in the literature. We describe, for the first time, a triad of AI, bilateral nephrolithiasis and FGF-23-mediated hypophosphataemia in LOF mutation of FAM20A. We suggest that serum phosphate should be measured in all patients with ERS to avoid metabolic and skeletal complications of undiagnosed, hence untreated hypophosphataemia.

Histopathological Evidence of Thyroid Dermopathy and its Correlation with Thyroid-Associated Orbitopathy in Patients with Graves' Disease having Normally Appearing Pretibial Skin: A Case-Control Study.

Objective: Thyroid dermopathy (TD), reportedly encountered in less than 5% of patients with Graves' disease (GD), is supposed to coexist only with thyroid-associated orbitopathy (TAO). However, clinically inapparent TD, detected non-invasively by thermal imaging or ultrasonography, seems to be present in a larger proportion of GD. Histopathological examination (HPE), though considered as gold standard for detecting TD, has not been performed widely to identify subclinical TD in GD. Materials and Methods: In this single-centre, cross-sectional, case-control study, 50 patients with GD (cases) and normal appearing pretibial skin were compared with 45 age- and sex-matched individuals (39 healthy volunteers, 3 with toxic multinodular goitre and 3 with solitary toxic nodule) (control). All patients were evaluated clinically for presence of TAO. Punch biopsy specimens were obtained from the pretibial skin in all 95 participants. Tissue sections were examined under light microscopy for mucin deposition, splitting of collagen fibrils and perivascular lymphocytic infiltration. Results: Sixty per cent of patients with GD demonstrated at least one of the above three histological features, while 52% had any combination of two features and 46% harboured all the three features. Mucin deposition, splitting of collagen fibrils and lymphocytic infiltration were found overall in 52%, 54% and 52% of GD, respectively; 4.4-11.1% of controls also had some evidence of TD on HPE. Subclinical TD was not related to age, duration of disease and TAO in our study. Conclusions: TD, particularly in its subclinical form, Seems to be widely prevalent in GD (46-60%) and exists even in absence of TAO. HPE, though more sensitive than the various non-invasive tests, is not specific (ranges from 89% to 95%) for TD. However, HPE can accurately diagnose TD in appropriate clinical background.

Secondary distal renal tubular acidosis and sclerotic metabolic bone disease in seronegative spondyloarthropathy.

Adults with distal renal tubular acidosis (dRTA) commonly present with hypokalaemia (with/without paralysis), nephrolithiasis/nephrocalcinosis and vague musculoskeletal symptoms. All adults with dRTA should be thoroughly evaluated for systemic diseases, certain medications and toxins. The leading cause of acquired or secondary dRTA in adults is primary Sjögren syndrome (SS); however, other collagen vascular diseases (CVDs) including seronegative spondyloarthropathy (SSpA) may at times give rise to secondary dRTA. Metabolic bone disease is often encountered in adults with dRTA, and the list includes osteomalacia and secondary osteoporosis; sclerotic metabolic bone disease is an extremely rare manifestation of dRTA. Coexistence of dRTA and sclerotic bone disease is seen in primary dRTA due to mutation in CA2 gene and acquired dRTA secondary to systemic fluorosis. Primary SS and SSpA, rarely if ever, may also lead to both secondary dRTA and osteosclerosis. Circulating autoantibodies against carbonic anhydrase II and possibly calcium sensing receptor may explain both these features in patients with CVD.

Desmopressin treatment in dipsogenic form of primary polydipsia: keep serum osmolality marginally below thirst threshold for symptomatic relief.

Dipsogenic polydipsia (DP), a distinct variety of primary polydipsia, is characterised by selective diminution of osmotic threshold for thirst leading to polydipsia and subsequent hypotonic polyuria. Seen in patients without underlying psychiatric illness, DP closely mimics central diabetes insipidus (CDI), making it difficult for clinicians to discriminate these two conditions from each other. Carefully performed osmotic stimulation study, incorporating objective assessment of threshold for thirst and arginine vasopressin (AVP) release is the key to differentiate DP from CDI or psychogenic polydipsia, also termed compulsive water drinking (CWD). Low thirst threshold and high AVP release threshold separate DP from CDI and CWD, respectively. Unlike CWD, desmopressin may be successfully used in DP without concomitant risk of hyponatremia. We describe a child, in whom an initial diagnosis of partial CDI was subsequently revised to DP based on osmotic stimulation test. The child was treated successfully with desmopressin therapy with a target to keep serum osmolality close to thirst threshold.

Clinical and Biochemical Characteristics of Patients with Renal Tubular Acidosis in Southern Part of West Bengal, India: A Retrospective Study.

PURPOSE OF THE STUDY: Reversible proximal tubular dysfunction associated with distal renal tubular acidosis (dRTA) mimics type 3 RTA, a condition classically associated with features of both proximal RTA (pRTA) and dRTA. Proximal tubulopathy has been reported in children with primary dRTA, but the data in adults are lacking. STUDY DESIGN: In this hospital record-based retrospective study, data from 66 consecutive cases of RTA, between January 2016 to December 2018, were retrieved and analyzed. RESULTS: Mean age of the study population was 25.3 years (range: 3 months to 73 years). Six (9.1%) of them had pRTA, 58 (87.9%) had dRTA, 1 (1.5%) had type 3 RTA, and the remaining 1 (1.5%) had type 4 RTA. Ten patients (17.2%) with dRTA and 3 patients of pRTA (50%) had underlying secondary etiologies. Data on proximal tubular dysfunction were available for 30 patients with dRTA, of whom 1 had isolated dRTA, and the rest 29 patients had accompanying completely reversible proximal tubular dysfunction. Among the 10 cases of secondary dRTA, 6 were not evaluated for proximal tubular dysfunction. Of the remaining 4, 3 had reversible form of proximal tubular abnormality. Fifty-two patients with dRTA came from a population, indigenous to the "Rarh" region of India. CONCLUSIONS: Proximal tubular dysfunction often accompanies dRTA; 75% of the children with primary dRTA, at least 29% of adults with primary dRTA, and at least 30% of adults with secondary dRTA manifest such completely reversible form of proximal tubulopathy. "Rarh' region of India probably is a hotspot for endemic dRTA.

Diabetes Monotherapies versus Metformin-Based Combination Therapy for the Treatment of Type 2 Diabetes.

Step-wise addition of antihyperglycemic agents (AHA) after the initiation of metformin monotherapy has been the traditional approach for the treatment of type 2 diabetes mellitus (T2DM) world-wide. Emerging evidence increasingly suggests that metformin-based combination therapy, especially with the newer AHA that lowers HbA1c glucose-dependently and do not potentiate hypoglycemia, could be a potentially better option for durable glycemic control with good tolerability compared to diabetes monotherapy. In this review, we descriptively analyzed the evidence available from the systematic reviews and meta-analyses of randomized head-to-head trials that reported the efficacy and safety outcomes of diabetes monotherapy, metformin-based combination therapies, and monotherapy versus metformin-based combination therapies.

Continuous and progressive 'wash-in' without 'wash-out' of contrast in adrenal mass: a useful feature of ganglioneuroma.

Computed tomography (CT) scan is a useful and widely performed diagnostic modality to evaluate adrenal masses. Nature of the mass determines the degree of attenuation both in unenhanced and in different phases of contrast enhancement. Benign neurogenic tumours like ganglioneuroma mimicks pheochromocytoma and adrenocortical carcinoma in non-contrast CT scan. The 'adrenal protocol' routinely calculates the wash-out pattern at delayed venous phase (DVP) (15 min) following contrast administration to differentiate majority of benign masses from the malignant ones. Ganglioneuromas typically exhibit continuous wash-in of contrast where enhancement gradually increases to attain its peak in DVP. Such wash-in pattern is different from the wash-out pattern observed in pheochromocytomas or adrenocortical adenomas or carcinomas. Presence of this wash-in pattern provides a useful clue to the clinician for underlying ganglioneuroma in hormonally inactive adrenal masses with suspicious morphological appearances. This wash-in pattern also effectively rules out any malignant potential of ganglioneuroma, and thus helps in preoperative decision-making.