Search

Background and purpose: Mutations in the early growth response 2 gene (EGR2) cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc finger (ZNF) DNA‐binding domain. The aim of this study was to provide a clinical and molecular analysis of a novel recessive mutation in EGR2. Methods: Clinical and electrophysiological assessments of three affected patients, from a consanguineous family, were performed. Genetic analyses of EGR2 were carried out by Sanger sequencing. Functional effects of clinical recessive mutations were assessed using a mammalian two‐hybrid assay. Results: A novel missense mutation (c.791C>T; p.P264L) in the homozygous state was detected outside the ZNF domains of the EGR2 gene. Three affected siblings presented with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. Respiratory compromise and cranial nerve dysfunction were also found. Our data indicate that the p.P264L mutation prevents interaction of EGR2 transcription factor with NAB corepressors, suggesting that a disruption of the NAB‐EGR2 protein interactions can result in dramatic neuropathy. Conclusion: Mutations in, or next to, the R1 domain of EGR2 should be considered with extreme caution for genetic counseling, since these could cause a severe neuropathy with an autosomal recessive manner of transmission. [ABSTRACT FROM AUTHOR]

Objectives: To describe the population of women having bariatric surgery and compare the pregnancy outcomes for women having bariatric surgery with a non-bariatric surgery population having a first and second pregnancy.Design: Population-based record linkage study.Setting: New South Wales (NSW), Australia.Population: All women aged 15-45 years with a hospital record in NSW (2002-2014) and all women giving birth in NSW (1994-2015; n = 1 606 737 women).Methods: Pregnancy and birth outcomes were compared between first and second pregnancies using repeated-measures logistic regression and paired Student's t-tests. Bariatric and non-bariatric groups were also compared.Main Outcome Measures: Maternal diabetes, preterm birth (<37 weeks of gestation) and large for gestational age.Results: There was a 13-fold increase in hospitalisations for primary bariatric surgery during 2002-2014. Compared with the general birthing population, women who had bariatric surgery experienced higher rates of hypertension, diabetes, and preterm birth. Among women who had bariatric surgery between a first and second pregnancy, there were reduced rates of hypertension (OR 0.39, 95% CI 0.29-0.53), spontaneous preterm birth (OR 0.37, 95% CI 0.16-0.86), infants that were large for gestational age (OR 0.63, 95% CI 0.44-0.88), and the admission of infants to a special care nursery or neonatal intensive care (OR 0.64, 95% CI 0.46-0.90) in the second pregnancy. Rates for small-for-gestational age and gestational diabetes following surgery were 8.3 and 11.4%, respectively CONCLUSIONS: Bariatric surgery between a first and second pregnancy was associated with reductions in obesity-related adverse pregnancy outcomes. Bariatric surgery performed for the management of obesity in accordance with current clinical criteria is associated with improved pregnancy outcomes in a subsequent pregnancy.Tweetable Abstract: Bariatric surgery for obesity may improve pregnancy and birth outcomes in a subsequent pregnancy. [ABSTRACT FROM AUTHOR]

Abstract: While guidelines support metformin as a therapeutic option for diabetic patients with mild‐to‐moderate renal insufficiency, the frequency and outcomes of metformin use in kidney transplant recipients are not well described. We integrated national U.S. transplant registry data with records from a large pharmaceutical claims clearinghouse (2008‐2015). Associations (adjusted hazard ratio, 95% LCLaHR95% UCL) of diabetes regimens (with and excluding metformin) in the first year post‐transplant with patient and graft survival over the subsequent year were quantified by multivariate Cox regression, adjusted for recipient, donor, and transplant factors and propensity for metformin use. Among 14 144 recipients with pretransplant type 2 diabetes mellitus, 4.7% filled metformin in the first year post‐transplant; most also received diabetes comedications. Compared to those who received insulin‐based regimens without metformin, patients who received metformin were more likely to be female, have higher estimated glomerular filtration rates, and have undergone transplant more recently. Metformin‐based regimens were associated with significantly lower adjusted all‐cause (aHR 0.180.410.91), malignancy‐related (aHR 0.450.450.99), and infection‐related (aHR 0.120.320.85) mortality, and nonsignificant trends toward lower cardiovascular mortality, graft failure, and acute rejection. No evidence of increased adverse graft or patient outcomes was noted. Use of metformin‐based diabetes treatment regimens may be safe in carefully selected kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a bifunctional protein comprising a TRP ion channel segment linked to an α-type protein kinase domain. TRPM7 is essential for proliferation and cell growth. Up-regulation of TRPM7 function is involved in anoxic neuronal death, cardiac fibrosis and tumour cell proliferation. The goal of this work was to identify non-toxic inhibitors of the TRPM7 channel and to assess the effect of blocking endogenous TRPM7 currents on the phenotype of living cells.Experimental Approach: We developed an aequorin bioluminescence-based assay of TRPM7 channel activity and performed a hypothesis-driven screen for inhibitors of the channel. The candidates identified were further assessed electrophysiologically and in cell biological experiments.Key Results: TRPM7 currents were inhibited by modulators of small conductance Ca²⁺ -activated K⁺ channels (K(Ca)2.1-2.3; SK) channels, including the antimalarial plant alkaloid quinine, CyPPA, dequalinium, NS8593, SKA31 and UCL 1684. The most potent compound NS8593 (IC₅₀ 1.6 µM) specifically targeted TRPM7 as compared with other TRP channels, interfered with Mg²⁺ -dependent regulation of TRPM7 channel and inhibited the motility of cultured cells. NS8593 exhibited full and reversible block of native TRPM7-like currents in HEK 293 cells, freshly isolated smooth muscle cells, primary podocytes and ventricular myocytes.Conclusions and Implications: This study reveals a tight overlap in the pharmacological profiles of TRPM7 and K(Ca)2.1-2.3 channels. NS8593 acts as a negative gating modulator of TRPM7 and is well-suited to study functional features and cellular roles of endogenous TRPM7. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a bifunctional protein comprising a TRP ion channel segment linked to an α-type protein kinase domain. TRPM7 is essential for proliferation and cell growth. Up-regulation of TRPM7 function is involved in anoxic neuronal death, cardiac fibrosis and tumour cell proliferation. The goal of this work was to identify non-toxic inhibitors of the TRPM7 channel and to assess the effect of blocking endogenous TRPM7 currents on the phenotype of living cells. EXPERIMENTAL APPROACH We developed an aequorin bioluminescence-based assay of TRPM7 channel activity and performed a hypothesis-driven screen for inhibitors of the channel. The candidates identified were further assessed electrophysiologically and in cell biological experiments. KEY RESULTS TRPM7 currents were inhibited by modulators of small conductance Ca2+-activated K+ channels (KCa2.1-2.3; SK) channels, including the antimalarial plant alkaloid quinine, CyPPA, dequalinium, NS8593, SKA31 and UCL 1684. The most potent compound NS8593 (IC50 1.6 µM) specifically targeted TRPM7 as compared with other TRP channels, interfered with Mg2+-dependent regulation of TRPM7 channel and inhibited the motility of cultured cells. NS8593 exhibited full and reversible block of native TRPM7-like currents in HEK 293 cells, freshly isolated smooth muscle cells, primary podocytes and ventricular myocytes. CONCLUSIONS AND IMPLICATIONS This study reveals a tight overlap in the pharmacological profiles of TRPM7 and KCa2.1-2.3 channels. NS8593 acts as a negative gating modulator of TRPM7 and is well-suited to study functional features and cellular roles of endogenous TRPM7. [ABSTRACT FROM AUTHOR]

The author discusses the need for a national quality improvement initiative to reduce the costs of liver transplantation in children in the United States. The author cites a University of Michigan study which reported on the financial implications of surgical complications in pediatric liver transplant recipients. The Michigan researchers have re-confirmed that surgical complications are expensive and lead to a financial burden to payers, medical centers and the government.

Objectives: To describe the population of women having bariatric surgery and compare the pregnancy outcomes for women having bariatric surgery with a non-bariatric surgery population having a first and second pregnancy., Design: Population-based record linkage study., Setting: New South Wales (NSW), Australia., Population: All women aged 15-45 years with a hospital record in NSW (2002-2014) and all women giving birth in NSW (1994-2015; n = 1 606 737 women)., Methods: Pregnancy and birth outcomes were compared between first and second pregnancies using repeated-measures logistic regression and paired Student's t-tests. Bariatric and non-bariatric groups were also compared., Main Outcome Measures: Maternal diabetes, preterm birth (<37 weeks of gestation) and large for gestational age., Results: There was a 13-fold increase in hospitalisations for primary bariatric surgery during 2002-2014. Compared with the general birthing population, women who had bariatric surgery experienced higher rates of hypertension, diabetes, and preterm birth. Among women who had bariatric surgery between a first and second pregnancy, there were reduced rates of hypertension (OR 0.39, 95% CI 0.29-0.53), spontaneous preterm birth (OR 0.37, 95% CI 0.16-0.86), infants that were large for gestational age (OR 0.63, 95% CI 0.44-0.88), and the admission of infants to a special care nursery or neonatal intensive care (OR 0.64, 95% CI 0.46-0.90) in the second pregnancy. Rates for small-for-gestational age and gestational diabetes following surgery were 8.3 and 11.4%, respectively CONCLUSIONS: Bariatric surgery between a first and second pregnancy was associated with reductions in obesity-related adverse pregnancy outcomes. Bariatric surgery performed for the management of obesity in accordance with current clinical criteria is associated with improved pregnancy outcomes in a subsequent pregnancy., Tweetable Abstract: Bariatric surgery for obesity may improve pregnancy and birth outcomes in a subsequent pregnancy., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Background: Suspected appendicitis is a common non-obstetric indication for emergency abdominal surgery during pregnancy., Aims: Assess the risk of preterm birth and other maternal and neonatal adverse birth outcomes following appendicectomy during pregnancy., Materials and Methods: Population-based data linkage study of women with singleton births in New South Wales, Australia, 2002-2014. Pregnancies with appendicitis and appendicectomy were compared to pregnancies without appendicitis. Crude and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for preterm birth were estimated. Modified Poisson regression with robust variance was used to estimate crude and adjusted risk ratios (aRR) with 99% CI for other outcomes., Results: Of 1 124 551 eligible pregnancies, 1024 (0.9/1000 pregnancies) had appendicitis and appendicectomy. Of these, 566 (55.3%) had laparoscopic and 458 (44.7%) had open appendicectomy. Appendicectomy at later gestational ages was associated with increasing rates of preterm birth. After adjustment for maternal and pregnancy factors, appendicectomy was associated with increased risk of preterm birth (overall aHR 1.73, 95% CI 1.42-2.09; planned aHR 2.08, 95% CI 1.60-2.72), maternal morbidity (aRR 2.68, 99% CI 1.88-3.83) and neonatal morbidity (aRR 1.42, 99% CI 1.03-1.94). However, there was no difference in perinatal mortality rates., Conclusion: Appendicectomy during pregnancy is associated with increased risk of spontaneous and planned preterm birth, maternal and neonatal morbidity. Availability of resources to prevent or manage preterm labour should be considered when appendicectomy is performed at gestational ages of 20 weeks or more., (© 2018 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Myogenic vasoconstriction (Bayliss effect) is mediated by vascular smooth muscle cells (VSMCs) of small resistance arteries sensing mechanical forces. During the last three decades, several proteins have been proposed as VSMC mechanosensors. Our previous studies highlighted agonist-independent mechanical activation of G q/11 protein-coupled receptors (G q/11 PCRs) in VSMCs of resistance arteries. In particular, angiotensin II AT1 receptors (AT 1 Rs) emerged as mechanosensors mediating myogenic tone. Moreover, we found that the AT 1B receptor isoform was more mechanosensitive than the AT 1A receptor. Interestingly, cysteinyl leukotriene 1 receptors (CysLT 1 Rs) were up-regulated in AT 1 R-deficient arteries as an essential backup strategy to compensate for the loss of vasoconstrictor receptors. Up-regulation of CysLT 1 Rs resulted in increased myogenic tone at low intraluminal pressures resulting in hyperactivity of AT 1 R-deficient arteries. Only at high intraluminal pressures myogenic tone was reduced, thus reflecting the loss of AT 1 Rs. Further, CysLT 1 Rs were involved in myogenic vasoconstriction of wild-type arteries. Simultaneous blockade of AT 1 Rs and CysLT 1 Rs in wild-type arteries caused reduction in myogenic tone of more than 60% comparable to the application of the selective G q/11 -protein inhibitor YM-254890. Our findings suggest that AT 1 Rs and CysLT 1 Rs are crucial mechanosensors in resistance arteries mediating 60% of myogenic vasoconstriction via the G q/11 -protein pathway without involvement of endogenous agonists., (© 2016 John Wiley & Sons Ltd.)

Background: Incisional hernias occur at surgical abdominal incision sites, but the association with caesarean section (CS) has not been examined., Aim: To determine whether CS is a risk factor for incisional hernia repair., Materials and Methods: Population-based cohort study in Australia using linked birth and hospital data for women who gave birth from 2000 to 2011. Survival analysis was used to explore the association between CS and subsequent incisional hernia repair. Analyses were adjusted for confounding factors, including other abdominal surgery. The main outcome measure was surgical repair of an incisional hernia., Results: Of 642,578 women, 217,555 (33.9%) had at least one CS and 1,554 (0.2%) women had a subsequent incisional hernia repair. The rate of incisional hernia repair in women who had ever had a caesarean section was 0.47%, compared to 0.12% in women who never had a caesarean section. After controlling for the duration of follow-up and known explanatory variables (eg other abdominal surgery, parity and multiple pregnancy), the adjusted hazard ratio (aHR) was 2.73 (95% confidence interval (CI) 2.45-3.06, P < 0.001). Incisional hernia repair risk increased with number of caesarean sections: women with two CS had a threefold increased risk of incisional hernia repair, which increased to sixfold after five CS (aHR = 6.29, 95% CI 3.99-9.93, P < 0.001) compared to women with no CS., Conclusions: There was a strong association between maternal CS and subsequent incisional hernia repair, which increased as the number of CSs increased, but the absolute risk of incisional hernia repair was low., (© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Coordinated release of calcium (Ca(2+) ) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress-induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca(2+) release from the SR causing arrhythmogenic delayed after depolarizations (DADs). Here, we report the generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation. In patient iPSC-derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca(2+) concentrations, a reduced SR Ca(2+) content and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca(2+) release events (Ca(2+) sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca(2+) spark properties and rescued the arrhythmogenic phenotype. This suggests defective inter-domain interactions within the RYR2 channel as the pathomechanism of the S406L mutation. Our work provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT., (Copyright © 2012 EMBO Molecular Medicine.)