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Abstract: Direct factor Xa (FXa) inhibitors lack a specific reversal agent for emergencies such as major bleeding or urgent surgery. Andexanet alfa, a modified, catalytically inactive, recombinant human FXa derivative, reverses anticoagulant effect by binding and sequestering FXa inhibitors. This original report of safety and dose-finding, phase 1 and 2 randomized, double-blind, placebo-controlled studies, investigated various doses of andexanet in healthy volunteers. Phase 1 evaluated the safety and pharmacokinetics of andexanet (n = 24) or placebo (n = 8). In phase 2, andexanet (n = 36) or placebo (n = 18) was administered following steady-state apixaban dosing (5 mg twice daily for 6 days); safety, pharmacokinetics, and pharmacodynamics were assessed. Andexanet plasma concentration increased proportionally with dose, with rapid elimination (terminal elimination half-life, 4.35-7.5 hours). Following apixaban treatment, andexanet rapidly (≤2 minutes) and dose dependently reduced unbound apixaban concentration vs placebo (51% to 89% vs 5% reduction; all P ≮ .05), decreased anti-FXa activity (67.8% to 95.0% vs 7.1% reduction; all P ≮ .05), and restored thrombin generation in 67% to 100% vs 6% of subjects (all P ≮ .01), maintaining these effects during continuous 45- and 120-minute infusions. Andexanet was well tolerated. Nine subjects had mild/moderate infusion reactions not associated with hemodynamic changes or respiratory compromise that generally resolved without intervention or dose reduction. There were no thrombotic events or other serious safety issues. In conclusion, andexanet reversed apixaban-mediated effects on pharmacodynamic markers of anticoagulation in healthy volunteers within minutes after administration and for the duration of infusion. This trial was registered at www.clinicaltrials.gov as #NCT01758432.

Context: Polycystic ovarian syndrome (PCOS), the most common endocrinopathy of women in the reproductive age group seems to be adversely affected by associated thyroid dysfunction. Both pose independent risks of ovarian failure and pregnancy related complications. Aims: The present study from Eastern India is, therefore, aimed to investigate the prevalence and etiology of different thyroid disorders in PCOS subjects. Settings and Design: Cross-sectional hospital based survey-single centre observational case-control study. Materials and Methods: This prospective single-center study recruited 106 female patients with hypertrichosis and menstrual abnormality among which 80 patients were defined as having PCOS according to the revised 2003 Rotterdam criteria and comprised the study population. Another 80 age-matched female subjects were studied as the control population. Thyroid function and morphology were evaluated by measurement of serum thyroid stimulating hormone (TSH), free thyroxine levels (free T3 and free T4), anti-thyroperoxidase antibody (anti-TPO Ab), clinical examination and ultrasound (USG) of thyroid gland. Statistical Analysis Used: It was done by Student′s t-test and Chi-square test using appropriate software (SPSS version 19). Results: This case-control study revealed statistically significant higher prevalence of autoimmune thyroiditis, detected in 18 patients (22.5% vs. 1.25% of control) as evidenced by raised anti-TPO antibody levels (means 28.037 ± 9.138 and 25.72 ± 8.27 respectively; P = 0.035). PCOS patients were found to have higher mean TSH level than that of the control group (4.547 ± 2.66 and 2.67 ± 3.11 respectively; P value < 0.05). There was high prevalence of goiter among PCOS patients (27.5% vs. 7.5% of control, P value < 0.001). On thyroid USG a significantly higher percentage of PCOS patients (12.5%; controls 2.5%) had hypoechoic USG pattern also compatible with the diagnosis of autoimmune thyroiditis. Conclusions: High prevalence of thyroid disorders in PCOS patients thus points towards the importance of early correction of hypothyroidism in the management of infertility associated with PCOS.

Leptin therapy in human recombinant form has recently been used in HIV-associated lipodystrophy syndrome on experimental basis in some small short-term clinical trials. It has shown its beneficial effects only in hypoleptinemic HIV-infected patients by causing definite improvement in their insulin sensitivity, glucose tolerance, lipid status, and truncal obesity. Leptin prevents lipotoxicity and activates insulin signaling pathways through several postulated mechanisms. Central leptin insufficiency with peripheral hyperleptinemia has come out to be a significant contributor to the development of obesity and metabolic syndrome. In this article, we will review the basis of leptin therapy in HIV patients, with its promises. However, further larger clinical trials are needed to prove its long-term efficacy in the control of metabolic complications related to HIV therapy.

Human immunodeficiency virus (HIV) endocrinopathy encompasses a broad spectrum of disorders. Almost all the endocrine organs are virtually affected by HIV infection. HIV can directly alter glandular function. More commonly secondary endocrine dysfunction occurs due to opportunistic infections and neoplasms in immunocompromised state. The complex interaction between HIV infection and endocrine system may be manifested as subtle biochemical and hormonal perturbation to overt glandular failure. Antiretroviral therapy as well as other essential medications often result in adverse endocrinal consequences. Apart from adrenal insufficiency, hypogonadism, diabetes and bone loss, AIDS wasting syndrome and HIV lipodystrophy need special reference. Endocrinal evaluation should proceed as in other patients with suspected endocrine dysfunction. Available treatment options have been shown to improve quality of life and long-term mortality in AIDS patients.

Hypothyroidism presenting as recurrent hypokalemic paralysis is rare in the literature. This transient and episodic neurological condition is commonly associated with thyrotoxicosis. We report a case of young female admitted with recurrent paralytic attacks since last 1 year. She had no symptom of hypothyroidism. She had weakness of all four limbs, delayed relaxation of ankle jerks, and normal higher mental function. There was no enlargement of thyroid. Serum potassium level ranged from 1.6 to 3.2 meq/L during attack with high serum creatine phosphokinase level. Electromyography was normal. The patient was diagnosed having chronic thyroiditis with high thyroid-stimulating hormone and thyroid-related antibodies. Follow up shows satisfactory result with thyroxine replacement. It is an extremely rare and unusual presentation of hypothyroidism, probably the fourth reported case of hypothyroidism with hypokalemic paralysis, to the best of our knowledge.

Acromegaly is diagnosed clinically by the universal presence of acral enlargement and typical coarse facies. We report a short, elderly female developing acromegalic facies for last 10 years without acral overgrowth. She is a patient of primary hypothyroidism, well controlled for last 20 years. Acromegaly was proven by high level of serum insulin like growth factor-1 (IGF-1) and elevated and nonsuppressed level of growth hormone (GH), with other hormonal profile being undisturbed. She had mild insulin resistance and systemic hypertension in absence of any visual field defect. Magnetic resonance imaging (MRI) of brain revealed pituitary hyperplasia without any detectable adenoma. No source of ectopic secretion of GH or growth hormone releasing hormone (GHRH) could be localized. Therefore, atypical presentation of acromegaly needs high degree of suspicion even if some of the common features are lacking. Here, we have biochemically proved acromegaly with typical facies, short stature but no acral overgrowth and pituitary adenoma despite longstanding disease activity, and thus eluding diagnosis for years.

Background: There is a dearth of studies on non-motor symptoms of Wilson's disease (WD) which is primarily because of the non-availability of a suitable scale. Objective: To assess the suitability of the Parkinson's Disease non motor symptoms questionnaire (PD-NMS Quest) in the assessment of non-motor symptoms of WD patients. Methods: In this case-control study, patients of WD above ≥12 years of age diagnosed by Leipzig's criteria and age and gender-matched control subjects were recruited. Critically ill patients, patients with severe hepatic impairment, or with pure hepatic WD were excluded. PD-NMS Quest was applied and relevant statistical analyses were performed. Results: A total of 18 cases and 25 controls were studied. Patients had a mean age of 22.6 years and a median disease duration of 8 years. WD patients had higher frequencies of all NMS than controls. Drooling (P = 0.0037), dysphagia or choking (P = 0.0088), nocturia (P = 0.0471), anxiety/fear (P = 0.0337), feeling sad or blue (P = 0.0020) and falling (P = 0.0197) were significantly higher in WD patients than controls. Conclusions: Although many NMS of WD patients are picked up effectively with PD-NMS Quest, some of them need detail assessment including cognitive, behavioral, and psychiatric symptoms, drooling and dysphagia, sleep as well as autonomic disturbances. Questions pertaining to sexual activity may be omitted from the questionnaire.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of motor neurons. Spread of pathology to other brain areas leads to development of non-motor symptoms (NMSs). These usually remain undiagnosed because of overwhelming motor problem and are responsible for significant distress to the patient. Our objective was to explore the burden of various NMSs of patients with ALS, compare between limb-onset and bulbar-onset patients, and to correlate with severity and duration of disease. Methods: Fifty patients with ALS diagnosed according to revised El Escorial Criteria and 50 healthy controls were included in this study. They were assessed with NMS Questionnaire, Beck's Depression Inventory, Center for Neurologic Study-Lability Scale, Drooling Frequency and Severity Scale, Epworth Sleepiness scale, Bengali Mental State Examination, and Frontal Assessment Battery and relevant statistical analyses were carried out. Results: The patients with ALS had significantly increased prevalence of almost all NMSs compared to controls. There was also significant increase in depression, suicidal ideation, pseudobulbar affect, and daytime sleepiness in patients with ALS. The bulbar onset subgroup had significantly increased daytime drooling, dysphagia, nausea and vomiting, whereas the limb onset subgroup reported increased frequency of leg swelling. Executive dysfunction was detected in 24% of patients with ALS and 9.8% had mild cognitive impairment. Weight loss, frequency of falling, insomnia, unpleasant nocturnal leg sensations, difficulty having sex, depression, and cognitive impairment increased significantly with an increase in severity of the disease. Conclusion: NMSs were significantly more prevalent in patients with ALS. Some NMSs worsened with advancement of the disease.

Context: Worldwide, the association of Vitamin D deficiency in Parkinson's disease (PD) has recently been proposed. However, to the best of our knowledge, such studies are lacking from eastern India. Aims: This study compares the prevalence of Vitamin D deficiency in a cohort of patients with PD with the prevalence in age-matched healthy controls. It also aimed at determining a significant correlation of the severity of the various motor manifestations in PD with low serum vitamin levels. Settings and Design: It was a prospective observational case–control study to estimate the level of serum 25-hydroxyvitamin D (25[OH] D) concentrations of the sample population. Subjects and Methods: One hundred consecutive PD patients were selected for this study between 2015 and 2018 from the patients attending neurology outpatient department. Control (n = 100) participants were randomly selected after matching for age sex, and geographic location. Statistical Analysis Used: Statistical Package for the Social Sciences version 15 with multivariate logistic regression (the Pearson correlation coefficient (r) and P value) was applied. Results: Among 100 PD patients 48, patients (48%) had Vitamin D deficiency, 34 patients (34%) had Vitamin D insufficiency, and 18 patients (18%) had normal Vitamin D level; whereas age- and sex-matched control population shows Vitamin D deficiency in 46% people, normal vitamin level in 42%, and insufficient Vitamin D level in 12% control population. The mean (standard deviation) 25(OH) D concentration in the PD cohort was significantly lower than in the control cohorts (20.72 [8.21] ng/mL vs. 25.56 [11.99] ng/mL, respectively; P = 0.001). There was major association between 25(OH) D levels and severity of motor scores (P = 0.028), tremor (P = 0.0001), bradykinesia (P = 0.001), and severity of freezing (P = 0.002), whereas no significant association was found between Vitamin D levels and rigidity (P = 0.05) and postural instability (P = 0.395). Conclusions: This study demonstrates a significantly higher prevalence of hypovitaminosis in PD versus healthy controls. The severity of motor scores, tremor, and bradykinesia and severity of freezing were found to have a direct inverse correlation with low serum Vitamin D levels which further emphasizes the provision of preventive and therapeutic supplementation of Vitamin D in PD.

Background and Aims: To study the clinical profile of genetically proven Huntington's disease (HD) patients from eastern India. Methods: This cross sectional study selected patients of HD after genetic confirmation of expanded CAG repeats in Huntingtin (HTT) gene. We performed detail clinical evaluation including cognitive and neuropsychological assessment, and imaging of brain. Results: This study included 75 patients (male: 57.3%; female: 42.7%). Mean age at onset was 37.12 (range 16-62) years; juvenile variety (onset below 20 years) was detected in 5.3%. Paternal transmission was commoner. Manifestations at onset were motor in 81.3% patients, behavioral in 10.7% and cognitive impairment in 8%. After chorea, next common movement disorder was dystonia. Frontal lobe dysfunction was found in 77.3% patients. Behavioral disturbances were observed in 77.3% patients and commonly manifested as depression, irritable behavior and anxiety. Among the three onset groups (motor/behavioral/cognitive), there was no significant difference regarding age at onset, gender distribution, pattern of inheritance (paternal/maternal), and at the time of evaluation, all groups had essentially similar pattern of clinical features. Mean CAG repeat of the patients was 48.25 (range 40-79). Our study showed some differing clinical characteristics compared to previous studies from the Indian subcontinent. Conclusion: Clinical features in our study showed differences from previous studies from the Indian subcontinent. We had more cognitive-onset patients. However, behavioral onset was lower in our study. Motor, behavioral and cognitive onset groups of HD were comparable regarding demographics, family history, CAG repeat lengths and major clinical features at the time of evaluation.

Whereas adaptive immunity has been extensively studied, very little is known about the innate immunity of the host to HTLV-I infection. HTLV-I-infected ATL patients have pronounced immunodeficiency associated with frequent opportunistic infections, and in these patients, concurrent infections with bacteria and/or parasites are known to increase risks of progression to ATL. The Toll-like receptor-4 (TLR4) activation in response to bacterial infection is essential for dendritic cell maturation and links the innate and adaptive immune responses. Recent reports indicate that TLR4 is targeted by viruses such as RSV, HCV, and MMTV. Here we report that HTLV-I has also evolved a protein that interferes with TLR4 signaling; p30 interacts with and inhibits the DNA binding and transcription activity of PU.1 resulting in the down-regulation of the TLR4 expression from the cell surface. Expression of p30 hampers the release of pro-inflammatory cytokines MCP-1, TNF-α, and IL-8 and stimulates release of anti-inflammatory IL-10 following stimulation of TLR4 in human macrophage. Finally, we found that p30 increases phosphorylation and inactivation of GSK3-β a key step for IL-10 production. Our study suggests a novel function of p30, which may instigate immune tolerance by reducing activation of adaptive immunity in ATL patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder long considered a diagnosis of exclusion. It is associated with decreased quality of life and significant economic burden to both the individual patient and society. To the best of our knowledge, this was the first study from this part of India assessing the relative impact on quality of life with respect to subtype of IBS. Subjects and Methods: The study was conducted between December 2011 and December 2013 among 1000 IBS patients attending general medical outpatient department of a tertiary care hospital in Kolkata (West Bengal, India). The Rome III criterion was used for diagnosis of IBS. IBS was further classified as diarrhea predominant (IBS-D), constipation-predominant (IBS-C) and mixed variety (IBS-M). This was a prospective, observational, cross-sectional study to assess the demographic and socioeconomic parameters, and impact of IBS on the quality of life of the patients by using short form-36 (SF-36) questionnaire. Results: The study found that IBS-D (67.6%) was the most common type, followed by IBS-M (30.4%) and IBS-C (2%). The majority of patients were males (59.2%). Overall none of the demographic and socioeconomic parameters analyzed in the study was found to have any significant bearing on the subtype of IBS affecting them. Eight scales of the SF-36 questionnaire were individually analyzed and correlated with the different subtypes of IBS. IBS-D group had the worst scores while IBS-M had the best score of quality of life. The difference between IBS-D and IBS-M was found to be statistically significant (P < 0.001) on every aspect. Conclusions: The study highlights that IBS is a bio-psychosocial disorder with poor quality of life. Most of the patients of IBS reporting to physicians have IBS-D. The socioeconomic and demographic factors do not appear to be significant determinants in this condition. IBS-D causes worst impact on quality of living among all subtypes.

Adie's tonic pupil, though well known in literature is a rarity in practice. Few case reports have mentioned the occurrence of Adie's pupil during a migraine attack. We report a young female with a history of migraine without aura presenting with asymmetric pupils during migraine attack. Her right pupil was dilated, unresponsive to light with poor response to near reflex. She also had a bilateral loss of ankle jerks. In 0.125% pilocarpine test, the affected pupil responded significantly, and Holmes Adie's syndrome was diagnosed. The patient remained asymptomatic after adjustment of refraction of the right eye for the near vision. It is usually a benign condition. Early clinical detection of such condition is necessary to prevent unnecessary and costly investigations as well to reassure the patient.