Role of Genetic Testing in the Management of Indeterminate Thyroid Nodules in the Indian Setting.

The increased detection of thyroid nodules in the human population has led to an increase in the number of thyroid surgeries without an improvement in survival outcomes. Though the choice for surgery is straightforward in malignant thyroid nodules, the decision is far more complex in those nodules that get categorized into indeterminate thyroid nodules (ITN) by fine needle aspiration. Therefore, there is a pressing need to develop a tool that will aid in decision-making among the ITN. In this context, the development of various molecular testing (MT) panels has helped to confirm or rule out malignancy, reducing unnecessary surgeries and potentially guiding the extent of surgery as well. Currently, such tests are widely used among the Western population but these MT panels are not used by the South Asian population because of non-availability of validated panels and the high cost involved. There is a need to develop a suitable panel which is population-specific and validate the same. In this review, we would focus on current trends in the management of ITN among the South Asian population and how to develop a novel MT panel which is cost-effective, with high diagnostic accuracy obviating the need for expensive panels that already exist.

Soluble Endoglin and Syndecan-1 levels predicts the clinical outcome in COVID-19 patients.

Endothelial instability is reported to be involved in the pathogenesis of COVID-19. The mechanism that regulates the endothelial dysfunction and disease virulence is not known. Studies on proteins that are released into circulation by activated endothelial cells may provide some means to understand the disease manifestation. The study investigated the circulating levels of two molecules Endoglin (Eng) and Syndecan-1 (SDC-1) that are presumed to be involved in the maintenance of endothelial integrity and their association with hypercoagulation marker in COVID-19 patients. The serum levels of Eng, SDC-1, D-mer were evaluated using ELISA at the time of admission (DOA) and day 7 post-admission among COVID-19 patients (N = 39 with 17 moderate and 22 severe cases). Compared to the time of admission, there was an increase in sEng and sSDC1 levels in all COVID-19 cases on day 7 post admission. The serum levels of sEng and sSDC-1 was significantly (P ≤ 0.001 & P ≤ 0.01 respectively) elevated in severe cases including the four deceased group compared to moderate cases on day 7 post admission. Further, the study molecules showed a strong positive association (P ≤ 0.001) with the hypercoagulation marker D-mer. The results show an early shedding of the endothelial proteins sEng and sSDC-1 into circulation as a host response to the viral infection during the febrile phase of infection. Increased levels of sEng and sSDC-1 along with D-mer could be beneficial in predicting COVID-19 disease severity.

Predictors of Delayed Hyponatraemia After Surgery for Pituitary Tumour.

Delayed hyponatraemia(DH) is a common complication following trans-sphenoidal surgery(TSS) for pituitary tumour. We evaluated the prevalence of DH following TSS, and assessed the factors associated with DH, including early post-operative diabetes insipidus(EPDI). This retrospective study included 100 TSS for pituitary tumours in 98 patients, over a period of 26 months. Subjects were divided into two groups: those who developed hyponatraemia and those who did not develop hyponatraemia, during post-operative days 4 to 14. The clinical characteristics and peri-operative parameters were compared between the two groups, to identify factors predicting DH. The mean age of the patients was 42.0±13.6 years, 58 (59%) were females and 61 (61%) had functional tumours. Thirty-six patients(36%) developed DH following TSS of whom majority(58%) were diagnosed on post-operative days 7 and 8; only 8/36 (22%) were symptomatic. Syndrome of inappropriate antidiuretic hormone secretion(SIADH) was found to be the most common aetiology of DH. On logistic regression analysis, intra-operative cerebrospinal fluid(CSF) leak (OR 5.0; 95% CI 1.9-13.8; p=0.002), EPDI (OR 3.4; 95% CI 1.3-9.2; p=0.015) and peri-operative steroid use (OR 3.6; 95% CI 1.3-9.8; p=0.014) were found to be significantly associated with DH. In conclusion, EPDI, intra-operative CSF leak and peri-operative steroid use were significant predictors of DH. EPDI predicts moderate to severe hyponatraemia with 80% specificity but has low sensitivity(47%). As most patients have asymptomatic hyponatraemia, serum sodium measurement on POD 7 to 10 would be helpful to identify DH in patients at increased risk.

Losartan as a Steroid-Sparing Adjunct in a Patient With Features of Refractory Camurati-Engelmann Disease.

Objective: The treatment of Camurati-Engelmann disease (CED) involves the use of glucocorticoids, analgesics, and bisphosphonates; experience with the use of losartan is limited. Our objective was to describe the case of a patient diagnosed with CED whose symptoms remained refractory while on steroids and bisphosphonates and who was successfully treated with losartan. Case Report: A 27-year-old woman presented with bone pain involving her extremities and large joints for 1 year. Clinical examination revealed bone tenderness and proximal myopathy with elevated C-terminal peptide of type 1 collagen (1617 pg/mL; normal range, 137-573 pg/mL) and N-terminal propeptide of type 1 procollagen levels (163 ng/mL; normal range, 5.1-58.3 ng/mL). Calcium (9.4 mg/dL; normal range, 8.3-10.4 mg/dL), phosphate (3.4 mg/dL; normal range, 2.5-4.5 mg/dL), and parathyroid hormone (62 pg/mL; normal range, 8-80 pg/mL) levels were within the normal range. Radiographs showed hyperostosis involving the diaphyseal region of long bones of the lower and upper limbs, and a provisional diagnosis of CED was made. She was treated with prednisolone, 30 mg daily, with which she reported some improvement. As exogenous Cushing syndrome had developed in her because of prednisolone, its dose was tapered. Subsequently, her bone pain worsened. Thereafter, she was initiated on oral alendronate. Due to persistent pain, losartan was added, after which she had marked decrease in bone pain with a reduction in the C-terminal peptide of type 1 collagen (375 pg/mL) and N-terminal propeptide of type 1 procollagen (50 ng/mL) levels. Discussion: Occasionally, CED presents therapeutic challenges, and when its symptoms remain refractory to conventional doses of steroids and bisphosphonates, other options may be needed. The abovementioned patient was initiated on losartan, which acts by downregulation of transforming growth factor ß1, leading to the reduction in pain. Conclusion: Losartan downregulates transforming growth factor ß1 and may be offered as a steroid-sparing option in individuals diagnosed with CED if symptoms remain refractory to conventional treatment.

[2.2]Paracyclophane-Based TCN-201 Analogs as GluN2A-Selective NMDA Receptor Antagonists.

Recent studies have shown the involvement of GluN2A subunit-containing NMDA receptors in various neurological and pathological disorders. In the X-ray crystal structure, TCN-201 (1) and analogous pyrazine derivatives 2 and 3 adopt a U-shape (hairpin) conformation within the binding site formed by the ligand binding domains of the GluN1 and GluN2A subunits. In order to mimic the resulting π/π-interactions of two aromatic rings in the binding site, a [2.2]paracyclophane system was designed to lock these aromatic rings in a parallel orientation. Acylation of [2.2]paracyclophane (5) with oxalyl chloride and chloroacetyl chloride and subsequent transformations led to the oxalamide 7, triazole 10 and benzamides 12. The GluN2A inhibitory activities of the paracyclophane derivatives were tested with two-electrode voltage clamp electrophysiology using Xenopus laevis oocytes expressing selectively functional NMDA receptors with GluN2A subunit. The o-iodobenzamide 12 b with the highest similarity to TCN-201 showed the highest GuN2A inhibitory activity of this series of compounds. At a concentration of 10 µM, 12 b reached 36 % of the inhibitory activity of TCN-201 (1). This result indicates that the [2.2]paracyclophane system is well accepted by the TCN-201 binding site.

Myelofibrosis and Pancytopenia Associated With Primary Hyperparathyroidism.

OBJECTIVE: Primary hyperparathyroidism (PHPT) has varied clinical presentations. Hematologic abnormalities secondary to PHPT have been described before. However, pancytopenia as the initial presentation has rarely been reported. We report a patient with PHPT who presented for evaluation of pancytopenia. METHODS: Histopathology of the bone marrow at presentation is described. Bone biochemistry results and the hematologic profile before and after curative parathyroidectomy are presented. RESULTS: A 48-year-old woman presented with pancytopenia (hemoglobin, 6.3 g/dL; total leucocyte count, 3000 cells/mm3; and platelet count, 60 000 cells/mm3), and her bone marrow study showed marrow fibrosis. Biochemical evaluation revealed hypercalcemia (15.5 mg/dL), hypophosphatemia (2.2 mg/dL), and elevated total alkaline phosphatase (4132 U/L). Bone mineral density assessment by dual-energy X-ray absorptiometry scan revealed osteoporosis at all 3 sites, which was more severe in the distal one third of the forearm. Further investigations confirmed the diagnosis of PHPT (serum parathyroid hormone, 2082 pg/mL). Following curative parathyroidectomy, in addition to normalization of calcium, there was restoration of all 3 hematologic cell lines at 3 months. CONCLUSION: Pancytopenia may be a rare manifestation of PHPT. Thus, it may be prudent to evaluate the calcium profile in patients with chronic refractory anemia and pancytopenia.

Idiopathic systemic capillary leak syndrome - An often missed diagnosis.

Idiopathic systemic capillary leak syndrome (ISCLS) is a potentially fatal disorder characterised by 'attacks' of varying intensity of hypovolemic shock in association with haemoconcentration and hypoalbuminaemia. It is a disease of exclusion, and the severity of attacks may mimic sepsis at presentation. We report a case of a lady with recurrent attacks of ISCLS with at least two life-threatening episodes, having been treated elsewhere as a case of steroid insufficiency. The diagnosis is often challenging, and treatment of an acute episode involves the judicious use of fluids and vasopressors, as required. Prophylaxis to prevent further attacks is of varied success.

Synthesis of GluN2A-selective NMDA receptor antagonists with an electron-rich aromatic B-ring.

Glutamatergic N-Methyl-d-aspartate (NMDA) receptors are heterotetrameric ion channels that can be comprised of different subunits. GluN2A subunit-containing NMDA receptors are associated with diseases like anxiety, depression, and schizophrenia. However, the exact contribution of these NMDA receptor subtypes is still unclear. To understand better the role of the GluN2A-containing receptors, novel ligands were designed. In co-crystallization with the isolated binding site, TCN-201 (1) and analogs adopt a U-shape conformation with parallel orientation of rings A and B. In order to increase the π/π-interactions between these rings, ring B of TCN-201 was replaced bioisosterically by different electron-rich thiazole, oxazole, and isoxazole heterocycles. The inhibitory activity was measured by two-electrode voltage clamp experiments with Xenopus laevis oocytes expressing GluN2A-containing NMDA receptors. It was found that 21c, 31a, 37a, and 37b were able to inhibit the ion channel. The isoxazole derivative 37b was the most potent negative allosteric modulator displaying 40% of the TCN-201 activity at a concentration of 10 µM.

Trabecular Bone Score-An Emerging Tool in the Management of Osteoporosis.

Areal bone mineral density (aBMD) is currently the gold standard for the diagnosis of osteoporosis, however, it has its own pitfalls. Trabecular bone score (TBS), a novel tool in the evaluation of osteoporosis is an indirect indicator of bone microarchitecture. It is a textural index that evaluates pixel gray-level variations in the lumbar spine DXA (dual energy X-ray absorptiometry) image. Both cross-sectional and longitudinal studies have demonstrated that TBS may independently predict fragility fractures. TBS can also be used to adjust FRAX probabilities of fracture, though data available till date doesn't support any additional benefit. TBS also shows an improving trend with anti-osteoporotic treatment; however, the least significant change (LSC) is high that it takes more than 2 years for the change to manifest. TBS is also used in the evaluation of bone strength in cases of secondary osteoporosis. Though TBS predicts fracture risk independently in both genders, with the currently available data, it cannot be recommended as a standalone tool for decision regarding treatment of osteoporosis. TBS can be used as a tool to complement BMD in assessment of bone health. Additional studies are needed to assess its utility in clinical practice.

FRAX® with or without BMD and TBS predicts fragility fractures in community-dwelling rural southern Indian postmenopausal women.

This study from southern India showed that FRAX® with or without BMD or TBS predicted fragility vertebral fractures at a cut-off of ≥ 9% for major osteoporotic fracture and ≥ 2.5% for hip fracture with sensitivities of 77-88% and specificities of 55-72%. PURPOSE: There is limited information available with regard to utility of Fracture Risk Assessment Tool (FRAX® tool) in predicting fragility fractures in Indian postmenopausal women. We studied the performance of 3 categories: FRAX® (without BMD), FRAX® (with BMD), and FRAX® (with BMD and TBS) in predicting fragility vertebral fractures in rural postmenopausal women. MATERIAL AND METHODS: It was a cross-sectional study conducted at a south Indian tertiary care center. Rural postmenopausal women (n = 301) were recruited by simple random sampling. The risk for major osteoporotic fracture (MOF) and hip fracture (HF) was calculated individually for the 3 categories. The BMD (at lumbar spine and femoral neck) and vertebral fractures were assessed by a DXA (dual energy X-ray absorptiometry) scanner and TBS by TBS iNsight software. ROC curves were constructed, and area under curve (AUC), sensitivity and specificity of FRAX® scores, which would best predict prevalent vertebral fractures (moderate to severe), was computed. RESULTS: The mean (SD) age was 65.6(5.1) years. The prevalence of osteoporosis at spine was 45%, and femoral neck was 32.6%. Moderate to severe vertebral fractures was seen in 29.2% of subjects. The performance of all 3 categories for FRAX® (MOF) and FRAX® (HF) were good (AUC was 0.798, 0.806, and 0.800, respectively, for MOF) at a cut-off score of ≥ 9, and at a cut-off of ≥ 2.5 for HF, it was 0.818, 0.775, and 0.770, respectively. At these cut-offs, sensitivities were 77-89%, and specificities were 55-72% for predicting prevalent vertebral fractures. CONCLUSION: All three categories of FRAX® showed good performance in predicting fractures in Indian postmenopausal women. Thus, it may be utilized for decision regarding treatment and referral for osteoporosis.

Pamidronate-Encapsulated Electrospun Polycaprolactone-Based Composite Scaffolds for Osteoporotic Bone Defect Repair.

Bone fractures associated with osteoporosis are a major concern all over the world especially among the elderly population and postmenopausal women. Bisphosphonates (BPs) are widely used clinically for both treatment and prevention of osteoporosis despite their poor oral bioavailability and undesired side effects. Local delivery of BPs from polymeric scaffolds can improve the efficacy and overcome the undesirable side effects associated with oral bisphosphonate therapy. The aim of the present study is to explore the effectiveness of pamidronate (PDS) encapsulated electrospun polycaprolactone/polycaprolactone-polyethyleneglycol-polycaprolactone/nanohydroxyapatite (PCH) scaffolds in healing critical-size calvarial defects in an osteoporotic rat animal model. Prior to implantation studies, the effect of PDS on the fiber architecture, mechanical properties, and in vitro degradation behavior was evaluated. The in vitro release of PDS from PCH scaffolds in phosphate buffer saline (PBS) at 37 °C was monitored for a period of 21 days. An osteoporotic animal model was successfully developed in Wistar rats by bilateral ovariectomy. Results of micro CT (computed tomography) and blood serum analysis confirmed the osteoporotic model induction in rats. Critical-size calvarial defects of 8 mm size were created in osteoporotic rats, and the in vivo osteogenic efficacy of PCH-PDS scaffolds was evaluated by micro CT, histology, and histomorphometry. Micro CT analysis showed improved osseous tissue integration with the use of PDS-loaded PCH scaffolds after 12 week post implantation. Histology, density measurement using micro CT, and histomorphometry further substantiate that PCH-PDS scaffolds have the potential to be used for the repair of osteoporotic bone defects. Our findings revealed that incorporation of PDS onto PCH scaffolds provides a promising biomaterial that could be used for regenerating osteoporosis-related fractures.

McCune Albright syndrome: an endocrine medley.

McCune Albright syndromeis a rare disorder that presents with multiple endocrine abnormalities. We report the case of a 24-year-old woman who presented with right lower limb pain, with no preceding trauma or fracture. On examination she was noted to have coarsened facial features, acral enlargement, bitemporal hemianopia, galactorrhoea and multiple café-au-lait macules. She gave history of precocious puberty, having attained menarche at 7 years of age. Biochemical investigations revealed hyperprolactinaemia, with unsuppressed growth hormone levels following a glucose load and subclinical hyperthyroidism. Technetium-99m methylene diphosphonate bone scan showed polyostotic fibrous dysplasia, MRI of the brain showed a pituitary macroadenoma. Thus she was diagnosed to have McCune Albright syndrome with multiple endocrine manifestations. She was treated with parenteral zoledronate for her bony lesions and initiated on cabergoline for plurihormonal pituitary macroadenoma. She is planned to be on close follow-up to assess for clinical improvement and appearance of other manifestations.

A rare cause of familial exogenous Cushing syndrome.

Exogenous steroid use is the most common cause of Cushing syndrome. With the use of glucocorticoids(GC) for a variety of diseases, the indiscriminate use of this group of drugs has increased. We present a family from which both children were brought with features suggestive of Cushing syndrome. On evaluation, they were found to have suppressed hypothalamic pituitary adrenal (HPA) axis, signifying steroid use from exogenous sources. On further evaluation by a psychiatrist, the mother who was on treatment for chronic depression confessed that she had bought dexamethasone tablets over the counter, and administered the same, mixed with fruit juices to her sons. The family was counselled regarding the consequences of chronic steroid abuse and the children were started on replacement doses of prednisolone. Certain features like posterior subcapsular cataract, glaucoma, avascular necrosis of femur and psychosis are specific to exogenous Cushing syndrome. Despite efforts to understand the effects of long-term steroid treatment on the HPA axis, it is not yet clear as to which patients will have prolonged HPA axis suppression. The time taken for the recovery of HPA axis remains variable. Also, HPA axis suppression due to exogenous steroids may present as acute adrenal crisis. Hence, it is important to start these patients on replacement dose of steroids and also educate them regarding the increased requirement of steroids during stress.

An uncommon cause of dysphagia.

Lingual thyroid is an abnormal mass of ectopic thyroid tissue seen in the base of tongue caused due to aberrant embryological development. It is often asymptomatic but may cause local symptoms, such as dysphagia, dysphonia, and upper airway obstruction. In this case, we report a 13-year-old girl who presented with dysphagia and breathing difficulty. Local examination revealed thyroid tissue in the posterior aspect of the tongue. Thyroid scintigraphy showed abnormal tracer uptake at base of tongue. Hormonal test showed subclinical hypothyroidism. She was treated with Levothyroxine.

HDAC as onco target: Reviewing the synthetic approaches with SAR study of their inhibitors.

Even though one is moving towards the success in the discovery of efficient anti-cancer molecules, the drugs used in the treatment of various malignancies are found to possess toxicity and adverse reactivity in the human body that limit their use. The scientists all over the world are engaged in bringing up strategies that aim to develop small molecules that target the abnormal epigenetic factors. The discovery of the role of Histone deacetylases (HDACs) has promised to be a turning point in the treatment of various malignancies. Thus, the invention of potent and safe anticancer therapeutics agents with minimal adverse and side effects are still a major topic of concern and a huge number of research works have been reported in the past few years. This review has been written to discuss on the influence of Histone Deacetylases in cancer malignancies. We have tried to embrace majority of the developments made till date in the field of HDAC and its inhibitors herein. The drugs that are clinically applied, synthesis and SAR study that highlight the chemical groups responsible for evoking the HDAC inhibition and potential of various new classes of HDAC inhibitors (synthetic, hybrid and natural) have also been included.

Development assessment of HIV exposed children aged 6-18 months: a cohort study from North India.

HIV exposed children are vulnerable to developmental delay irrespective of their HIV status due to combined effect of risk factors like poverty, prenatal drug exposure, stress and chronic illness in family and malnutrition. This cohort study assessed the development of 50 HIV exposed children aged 6-18 months at a Pediatric Centre of Excellence in HIV care in India. The development was assessed using Development Assessment Scale for Indian Infants (DASII) at enrolment, 3 and 6 months later. The development quotient (DQ) scores and proportion of children with developmental delay (DQ ≤ 70) were compared among two sub-groups, HIV infected (HI) and HIV exposed uninfected (HEU) children. The various social and clinical factors affecting development were studied by univariate and multivariate analysis. Prevalence of developmental delay was 2.4% in the HEU (n = 41), and 33.3% in HI (n = 9). The DQ of HI was significantly lower than that of HEU at all three assessments. The DQ of HI were also significantly lower compared to the HEU at ages 12.1-18 months (83.37 ± 20.73 vs 94.68 ± 5.13, p = 0.005) and 18.1-24 months (84.55 ± 15.35 vs 94.63 ± 5.86, p = 0.006) respectively. The development of HEU was adversely affected by lower socioeconomic status and presence of wasting. In addition, development of HI was also adversely influenced by presence of stunting and opportunistic infections, advanced disease stage and shorter ART duration. We conclude that with optimum care, HEU can have a normal development, while a considerable proportion of HI may continue to have delayed development.