Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ.

CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.This study made use of data generated by the UK10K Project and we acknowledge the contribution of the UK10K Consortium. This work was supported by Wellcome Trust Grants 100585/Z/12/Z (to N.S.), and 095564/Z/11/Z (to V.K.C.) and the National Institute for Health Research Cambridge Biomedical Research Center (to V.K.C., N.S.). E.G.S and C.A.A. are supported by the Wellcome Trust (098051). Funding for the UK10K Project was provided by the Wellcome Trust under award WT091310

A retrospective analysis of glycol and toxic alcohol ingestion: utility of anion and osmolal gaps

<p>Abstract</p> <p>Background</p> <p>Patients ingesting ethylene glycol, isopropanol, methanol, and propylene glycol ('toxic alcohols') often present with non-specific signs and symptoms. Definitive diagnosis of toxic alcohols has traditionally been by gas chromatography (GC), a technique not commonly performed on-site in hospital clinical laboratories. The objectives of this retrospective study were: 1) to assess the diagnostic accuracy of the osmolal gap in screening for toxic alcohol ingestion and 2) to determine the common reasons other than toxic alcohol ingestion for elevated osmolal gaps.</p> <p>Methods</p> <p>Electronic medical records from an academic tertiary care medical center were searched to identify all patients in the time period from January 1, 1996 to September 1, 2010 who had serum/plasma ethanol, glucose, sodium, blood urea nitrogen, and osmolality measured simultaneously, and also all patients who had GC analysis for toxic alcohols. Detailed chart review was performed on all patients with osmolal gap of 9 or greater.</p> <p>Results</p> <p>In the study period, 20,669 patients had determination of serum/plasma ethanol and osmolal gap upon presentation to the hospitals. There were 341 patients with an osmolal gap greater than 14 (including correction for estimated contribution of ethanol) on initial presentation to the medical center. Seventy-seven patients tested positive by GC for one or more toxic alcohols; all had elevated anion gap or osmolal gap or both. Other than toxic alcohols, the most common causes for an elevated osmolal gap were recent heavy ethanol consumption with suspected alcoholic ketoacidosis, renal failure, shock, and recent administration of mannitol. Only 9 patients with osmolal gap greater than 50 and no patients with osmolal gap greater than 100 were found to be negative for toxic alcohols.</p> <p>Conclusions</p> <p>Our study concurs with other investigations that show that osmolal gap can be a useful diagnostic test in conjunction with clinical history and physical examination.</p

Table_1_Higher carbohydrate intake in relation to non-alcoholic fatty liver disease in patients with type 2 diabetes.docx

BackgroundNon-alcoholic fatty liver disease (NAFLD) is an overlooked complication of type 2 diabetes (T2D). Current recommendations for the management of NAFLD are mainly focused on weight reduction, overlooking the role of macronutrient composition. Although dietary carbohydrates play a major role in intrahepatic fat synthesis, their association with the progression of liver steatosis has not been fully investigated in patients with T2D.AimTo investigate the association between higher carbohydrate intake and the presence of liver steatosis in patients with T2D.MethodsThis cross-sectional study included men and women aged 18–60 years diagnosed with T2D. Anthropometric measurements, hepatic steatosis assessment using the controlled attenuation parameter (CAP), blood samples, and dietary data were analyzed. Participants were divided into two groups: NAFLD and NAFLD-free. A two-sample t-test was used to evaluate the differences between the two groups. Stepwise multiple linear regression models adjusted for potential confounders were used to determine the association between CAP values and higher carbohydrate intake.ResultsIn total, 358 participants were included. NAFLD was present in 79.3% of the participants. Body mass index, waist circumference, ALT, HbA1c, and triglycerides showed direct, while HDL-Cholesterol revealed inverse associations with CAP values. No significant relationship was found between carbohydrate intake and steatosis in the total study sample; however, multiple linear regression analysis revealed a significant relationship between carbohydrate intake and CAP values in patients aged ≤50 years.ConclusionIn patients with T2D, higher carbohydrate intake was associated with liver steatosis in those aged 50 years and below. Further studies are required to confirm the causality between carbohydrate intake and liver steatosis.</p

Comprehensive screening of eight known causative genes in congenital hypothyroidism with gland-in-situ

Context: lower thyroid-stimulating hormone (TSH) screening cut-offs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically-located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes, or the thyroid-stimulating hormone receptor (TSHR) underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.Objective: to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD and TSHR) in CH cases with GIS.Patients, Design and Setting: we screened forty-nine CH cases with GIS from thirty-four ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.Results: twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (nineteen cases) most commonly involved TG (twelve), TPO (four), DUOX2 (two) and TSHR (one case). Ten cases harboured triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three) and DUOX2 and TG (six cases). Novel variants overall included fifteen TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in twenty patients, including fourteen familial cases.Conclusions: the aetiology ofCHwith GIS remains elusive, with only59%attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (~41%) of unsolved or ambiguous cases suggests novel genetic aetiologies that remain to be elucidated- See more at: http://press.endocrine.org/doi/10.1210/jc.2016-1879#sthash.8M832MqP.dpu

Comprehensive screening of eight known causative genes in congenital hypothyroidism with gland-in-situ

Context: lower thyroid-stimulating hormone (TSH) screening cut-offs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically-located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes, or the thyroid-stimulating hormone receptor (TSHR) underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.Objective: to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD and TSHR) in CH cases with GIS.Patients, Design and Setting: we screened forty-nine CH cases with GIS from thirty-four ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.Results: twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (nineteen cases) most commonly involved TG (twelve), TPO (four), DUOX2 (two) and TSHR (one case). Ten cases harboured triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three) and DUOX2 and TG (six cases). Novel variants overall included fifteen TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in twenty patients, including fourteen familial cases.Conclusions: the aetiology ofCHwith GIS remains elusive, with only59%attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (~41%) of unsolved or ambiguous cases suggests novel genetic aetiologies that remain to be elucidated- See more at: http://press.endocrine.org/doi/10.1210/jc.2016-1879#sthash.8M832MqP.dpu

Complications of chronic alcoholism that affect critical illness

[An excerpt from the content] The worldwide consumption of alcohol and alcoholism, or alcohol use disorder (defined as a problematic pattern of alcohol use leading to clinically significant impairment or distress by DSM-5) [1], are increasing [2]. This is particularly so among women as the social stigma surrounding drinking declines and alcohol is more readily accessible. Women are less likely to be diagnosed early and more likely to relapse after treatment. Alcoholism is estimated to cause approximately 2.5 million global deaths annually (4 % of all-cause mortality) which mostly ensue from liver disease [2]. Approximately 90 % of alcoholics develop fatty liver, 25 % develop alcoholic hepatitis, 15 % develop cirrhosis and 10 % develop hepatocellular carcinoma [3, 4]. Alcoholic liver disease (ALD), especially cirrhosis, also accounts for increasing numbers of hospital admissions across the world, including ICU admissions [5, 6]. Each year about 26,000 patients with cirrh ..