Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations

Objective: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). Subjects and methods: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. Results: A genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. Conclusions: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded

A rotating three component perfect fluid source and its junction with empty space-time

The Kerr solution for empty space-time is presented in an ellipsoidally symmetric coordinate system and it is used to produce generalised ellipsoidal metrics appropriate for the generation of rotating interior solutions of Einstein's equations. It is shown that these solutions are the familiar static perfect fluid cases commonly derived in curvature coordinates but now endowed with rotation. The resulting solutions are also discussed in the context of T-solutions of Einstein's equations and the vacuum T-solution outside a rotating source is presented. The interior source for these solutions is shown not to be a perfect fluid but rather an anisotropic three component perfect fluid for which the energy momentum tensor is derived. The Schwarzschild interior solution is given as an example of the approach.Comment: 14 page

No more CKY two-forms in the NHEK

We show that in the near-horizon limit of a Kerr-NUT-AdS black hole, the space of conformal Killing-Yano two-forms does not enhance and remains of dimension two. The same holds for an analogous polar limit in the case of extremal NUT charge. We also derive the conformal Killing-Yano $p$-form equation for any background in arbitrary dimension in the form of parallel transport.Comment: 36 pages, 12 pdf figures, v2: minor change

Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation

Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc.Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clinical diagnostic testing from analysis of fewer than ten genes per phenotype to more than 100. Noncoding mutations have been less extensively studied despite evidence from mRNA analysis for the existence of deep intronic mutations in >20 genes. We investigated individuals with hyperinsulinaemic hypoglycaemia and biochemical or genetic evidence to suggest noncoding mutations by using NGS to analyze the entire genomic regions of ABCC8 (117 kb) and HADH (94 kb) from overlapping ~10 kb PCR amplicons. Two deep intronic mutations, c.1333-1013A>G in ABCC8 and c.636+471G>T HADH, were identified. Both are predicted to create a cryptic splice donor site and an out-of-frame pseudoexon. Sequence analysis of mRNA from affected individuals' fibroblasts or lymphoblastoid cells confirmed mutant transcripts with pseudoexon inclusion and premature termination codons. Testing of additional individuals showed that these are founder mutations in the Irish and Turkish populations, accounting for 14% of focal hyperinsulinism cases and 32% of subjects with HADH mutations in our cohort. The identification of deep intronic mutations has previously focused on the detection of aberrant mRNA transcripts in a subset of disorders for which RNA is readily obtained from the target tissue or ectopically expressed at sufficient levels. Our approach of using NGS to analyze the entire genomic DNA sequence is applicable to any disease

Characteristics of patients operated for primary hyperparathyroidism at university hospitals in Türkiye: Differences among Türkiye's geographical regions

Purpose: The aim of this study was to define the clinical and laboratory characteristics of patients operated on for primary hyperpatathyroidism (PHPT) at university hospitals in Türkiye, and to investigate the differences in the clinical presentations of the disease between different geographical regions. Methods: Patients operated on for PHPT in the university hospitals of Türkiye were included in the study. The demographic, clinical, and laboratory findings and the operational data of the patients were investigated according to the whole country and to different geographical regions. Comparisons were performed according to whole country and regions. Results: A total of 1,162 cases were included in the study from different regions and 20 university hospitals. The mean age of patients was 52.4 ± 0.38 (mean ± standard error) in the general population of Türkiye. The rates of hypertension, urolithiasis, bone disease and 25-hydroxyvitamin D insufficiency were 35%, 18.6%, 67.6%, and 63%, respectively. The median parathormone (PTH), serum total calcium (Ca+2) and phosphorus value were 220 pg/mL (range, 70-2,500 pg/mL), 11.2 mg/dL (range, 9.5-11.2 mg/dL), and 2.4 mg/dL (range, 1-4.7 mg/dL), respectively. The median size of the adenomas resected was 16 mm (range, 4-70 mm). Significant differences were observed in the clinical and laboratory findings of the patients operated on due to PHPT between different geographical regions of Türkiye (P < 0.05). Conclusion: The clinical and laboratory characteristics of the patients with PHPT in different geographical regions of Türkiye differ. Furthermore, the general findings of the cases in Türkiye give us a hint that the severity of the disease here is somewhere between Eastern and Western countries. Copyright © 2016, the Korean Surgical Society

Spin–orbit precession for eccentric black hole binaries at first order in the mass ratio

We consider spin–orbit ('geodetic') precession for a compact binary in strong-field gravity. Specifically, we compute ψ, the ratio of the accumulated spin-precession and orbital angles over one radial period, for a spinning compact body of mass m 1 and spin s 1, with ${{s}_{1}}\ll Gm_{1}^{2}/c$ , orbiting a non-rotating black hole. We show that ψ can be computed for eccentric orbits in both the gravitational self-force and post-Newtonian frameworks, and that the results appear to be consistent. We present a post-Newtonian expansion for ψ at next-to-next-to-leading order, and a Lorenz-gauge gravitational self-force calculation for ψ at first order in the mass ratio. The latter provides new numerical data in the strong-field regime to inform the effective one-body model of the gravitational two-body problem. We conclude that ψ complements the Detweiler redshift z as a key invariant quantity characterizing eccentric orbits in the gravitational two-body problem

Serum paraoxonase and arylesterase activities in patients with lung cancer in a Turkish population

BACKGROUND: Lung cancer (LC) is the leading cause of cancer-related deaths. Oxidative DNA damage may contribute to the cancer risk. The antioxidant paraoxonase (PON1) is an endogenous free radical scavenger in the human body. The aim of this study was to determine serum PON1 and arylesterase (ARE) activities in patients with newly diagnosed LC. METHODS: This case control study involved a total of 39 patients with newly diagnosed LC (untreated) and same number of age- and sex-matched healthy individuals. Serum PON1 and ARE activities in addition to lipid parameters were measured in both groups. RESULTS: Serum PON1 and ARE activities were found to be lower in patients with LC compared to the controls (p = 0.001 and p = 0.018, respectively). The ratio of PON1/high density lipoprotein (HDL) was significantly lower in the LC group compared to the control one (p = 0.009). There were positive correlations between the serum levels of HDL and PON1 in both the control (r = 0.415, p = 0.009) and the LC groups (r = 0.496, p = 0.001), respectively. PON1 enzyme activity was calculated as three different phenotypes in both groups. In regard to lipid parameters, total cholesterol levels were significantly lower (p = 0.014) in the LC group whereas the other lipid parameters such as HDL, LDL, and triglyceride levels were not significantly different among groups. CONCLUSION: Serum PON1 activity is significantly low in the LC group compared with the healthy controls. Metastasis status and cigarette smoking do not affect serum PON1 activity in the LC patients

Does Gender Influence Colour Choice in the Treatment of Visual Stress?

Purpose Visual Stress (VS) is a condition in which words appear blurred, in motion, or otherwise distorted when reading. Some people diagnosed with VS find that viewing black text on white paper through coloured overlays or precision tinted lenses (PTLs) reduces symptoms attributed to VS. The aim of the present study is to determine whether the choice of colour of overlays or PTLs is influenced by a patient’s gender. Methods Records of all patients attending a VS assessment in two optometry practices between 2009 and 2014 were reviewed retrospectively. Patients who reported a significant and consistent reduction in symptoms with either overlay and or PTL were included in the analysis. Overlays and PTLs were categorized as stereotypical male, female or neutral colours based on gender preferences as described in the literature. Chi-square analysis was carried out to determine whether gender (across all ages or within age groups) was associated with overlay or PTL colour choice. Results 279 patients (133 males and 146 females, mean age 17 years) consistently showed a reduction in symptoms with an overlay and were included. Chi-square analysis revealed no significant association between the colour of overlay chosen and male or female gender (Chi-square 0.788, p = 0.674). 244 patients (120 males and 124 females, mean age 24.5 years) consistently showed a reduction in symptoms with PTLs and were included. Chi-square analysis revealed a significant association between stereotypical male/female/neutral colours of PTLs chosen and male/female gender (Chi-square 6.46, p = 0.040). More males preferred stereotypical male colour PTLs including blue and green while more females preferred stereotypical female colour PTLs including pink and purple. Conclusions For some VS patients, the choice of PTL colour is influenced not only by the alleviation of symptoms but also by other non-visual factors such as gender