secCl is a cys-loop ion channel necessary for the chloride conductance that mediates hormone-induced fluid secretion in Drosophila

Organisms use circulating diuretic hormones to control water balance (osmolarity), thereby avoiding dehydration and managing excretion of waste products. The hormones act through G-protein-coupled receptors to activate second messenger systems that in turn control the permeability of secretory epithelia to ions like chloride. In insects, the chloride channel mediating the effects of diuretic hormones was unknown. Surprisingly, we find a pentameric, cys-loop chloride channel, a type of channel normally associated with neurotransmission, mediating hormone-induced transepithelial chloride conductance. This discovery is important because: 1) it describes an unexpected role for pentameric receptors in the membrane permeability of secretory epithelial cells, and 2) it suggests that neurotransmitter-gated ion channels may have evolved from channels involved in secretion

Unilateral leg swelling in a newborn

A female neonate was born with asymmetric lower limbs, the right leg appearing enlarged, with thickened, reddish-purple skin and ectasic superficial reticulum (figure 1A,B). Limb pulses were present and symmetrical. The girl's family history and prenatal scans were unremarkable. Laboratory findings were within the normal range, except for a mild thrombocytopenia (90 000/μL), which spontaneously resolved during the next few days. A leg X-ray and the Doppler analysis ruled out the presence of calcifications and venous varices, respectively. Ultrasound showed significant skin thickening, with marked dermal hypertrophy and hyperechogenicity. Magnetic resonance showed circumferential thickening of the derma, with mild hypertrophy of some perforating vessels (figure 2). A biopsy of the right thigh showed capillary malformations on histology. edpract;archdischild-2020-320450v1/BLKF1F1BLK_F1Figure 1(A, B) Hypertrophy of the right lower limb, with large capillary malformation extending to the gluteus and the external genitalia. edpract;archdischild-2020-320450v1/BLKF2F2BLK_F2Figure 2Axial THRIVE magnetic resonance scan of the thighs' proximal third, showing circumferential dermal thickening and inhomogeneity of the right leg's subcutaneous tissue. QUESTIONS: Based on the clinical picture and investigations results, which is the most likely diagnosis?Beckwith-WiedemannCLOVES syndromeKlippel-Trenaunay syndromeKaposiform hemangioendotheliomaHow can the diagnosis be confirmed?CT with PETLymphoscintigraphyGenetic testingNone of the above, the diagnosis is clinicalWhat is the mainstay of management?Conservative with follow-upPharmacotherapySclerotherapySurgeryWhich of the following complications can occur?ScoliosisGlaucomaUrinary and gastrointestinal bleedingAll of the above Answers can be found on page 02

Construction of a Resting High Fidelity ECG "SuperScore" for Management and Screening of Heart Disease

Resting conventional ECG is notoriously insensitive for detecting coronary artery disease (CAD) and only nominally useful in screening for cardiomyopathy (CM). Similarly, conventional exercise stress test ECG is both time- and labor-consuming and its accuracy in identifying CAD is suboptimal for use in population screening. We retrospectively investigated the accuracy of several advanced resting electrocardiographic (ECG) parameters, both alone and in combination, for detecting CAD and cardiomyopathy (CM)

Advanced Electrocardiography Can Identify Occult Cardiomyopathy in Doberman Pinschers

Recently, multiple advanced resting electrocardiographic (A-ECG) techniques have improved the diagnostic value of short-duration ECG in detection of dilated cardiomyopathy (DCM) in humans. This study investigated whether 12-lead A-ECG recordings could accurately identify the occult phase of DCM in dogs. Short-duration (3-5 min) high-fidelity 12-lead ECG recordings were obtained from 31 privately-owned, clinically healthy Doberman Pinschers (5.4 +/- 1.7 years, 11/20 males/females). Dogs were divided into 2 groups: 1) 19 healthy dogs with normal echocardiographic M-mode measurements: left ventricular internal diameter in diastole (LVIDd . 47mm) and in systole (LVIDs . 38mm) and normal 24-hour ECG recordings (100 VPCs/24h; 1/12 dogs had only abnormal 24-hour ECG recordings (>100 VPCs/24h). ECG recordings were evaluated via custom software programs to calculate multiple parameters of high-frequency (HF) QRS ECG, heart rate variability, QT variability, waveform complexity and 3-D ECG. Student's t-tests determined 19 ECG parameters that were significantly different (P < 0.05) between groups. Principal component factor analysis identified a 5-factor model with 81.4% explained variance. QRS dipolar and non-dipolar voltages, Cornell voltage criteria and QRS waveform residuum were increased significantly (P < 0.05), whereas mean HF QRS amplitude was decreased significantly (P < 0.05) in dogs with occult DCM. For the 5 selected parameters the prediction of occult DCM was performed using a binary logistic regression model with Chi-square tested significance (P < 0.01). ROC analyses showed that the five selected ECG parameters could identify occult ECG with sensitivity 89% and specificity 83%. Results suggest that 12-lead A-ECG might improve diagnostic value of short-duration ECG in earlier detection of canine DCM as five selected ECG parameters can with reasonable accuracy identify occult DCM in Doberman Pinschers. Future extensive clinical studies need to clarify if 12-lead A-ECG could be useful as an additional screening test for canine DCM

Conventional QT variability measurement vs. template matching techniques: comparison of performance using simulated and real ECG

Increased beat-to-beat variability in the QT interval (QTV) of ECG has been associated with increased risk for sudden cardiac death, but its measurement is technically challenging and currently not standardized. The aim of this study was to investigate the performance of commonly used beat-to-beat QT interval measurement algorithms. Three different methods (conventional, template stretching and template time shifting) were subjected to simulated data featuring typical ECG recording issues (broadband noise, baseline wander, amplitude modulation) and real short-term ECG of patients before and after infusion of sotalol, a QT interval prolonging drug. Among the three algorithms, the conventional algorithm was most susceptible to noise whereas the template time shifting algorithm showed superior overall performance on simulated and real ECG. None of the algorithms was able to detect increased beat-to-beat QT interval variability after sotalol infusion despite marked prolongation of the average QT interval. The QTV estimates of all three algorithms were inversely correlated with the amplitude of the T wave. In conclusion, template matching algorithms, in particular the time shifting algorithm, are recommended for beat-to-beat variability measurement of QT interval in body surface ECG. Recording noise, T wave amplitude and the beat-rejection strategy are important factors of QTV measurement and require further investigation.Mathias Baumert, Vito Starc and Alberto Port

WHO European Childhood Obesity Surveillance Initiative: body mass index and level of overweight among 6-9-year-old children from school year 2007/2008 to school year 2009/2010

Background: The World Health Organization (WHO) Regional Office for Europe has established the Childhood Obesity Surveillance Initiative (COSI) to monitor changes in overweight in primary-school children. The aims of this paper are to present the anthropometric results of COSI Round 2 (2009/2010) and to explore changes in body mass index (BMI) and overweight among children within and across nine countries from school years 2007/2008 to 2009/2010. Methods: Using cross-sectional nationally representative samples of 6−9-year-olds, BMI, anthropometric Z-scores and overweight prevalence were derived from measured weight and height. Significant changes between rounds were assessed using variance and t-tests analyses. Results: At Round 2, the prevalence of overweight (including obesity; WHO definitions) ranged from 18% to 57% among boys and from 18% to 50% among girls; 6 − 31% of boys and 5 − 21% of girls were obese. Southern European countries had the highest overweight prevalence. Between rounds, the absolute change in mean BMI (range: from −0.4 to +0.3) and BMI-for-age Z-scores (range: from −0.21 to +0.14) varied statistically significantly across countries. The highest significant decrease in BMI-for-age Z-scores was found in countries with higher absolute BMI values and the highest significant increase in countries with lower BMI values. The highest significant decrease in overweight prevalence was observed in Italy, Portugal and Slovenia and the highest significant increase in Latvia and Norway. Conclusions: Changes in BMI and prevalence of overweight over a two-year period varied significantly among European countries. It may be that countries with higher prevalence of overweight in COSI Round 1 have implemented interventions to try to remedy this situation

Resistance to neoplastic transformation of ex-vivo expanded human mesenchymal stromal cells after exposure to supramaximal physical and chemical stress

The risk of malignant transformation of ex-vivo expanded human mesenchymal stromal cells (huMSCs) has been debated in the last years; however, the biosafety of these cells after exposure to supramaximal physical and chemical stress has never been systematically investigated. We established an experimental in vitro model to induce supramaximal physical (ionizing radiation, IR) and chemical (starvation) stress on ex-vivo expanded bone marrow (BM)-derived huMSCs and investigated their propensity to undergo malignant transformation. To this aim, we examined MSC morphology, proliferative capacity, immune-phenotype, differentiation potential, immunomodulatory properties and genetic profile before and after stressor exposure. Furthermore, we investigated the cellular mechanisms underlying MSC response to stress. MSCs were isolated from 20 healthy BM donors and expanded in culture medium supplemented with 5% platelet lysate (PL) up to passage 2 (P2). At this stage, MSCs were exposed first to escalating doses of IR (30, 100, 200 Gy) and then to starvation culture conditions (1% PL). With escalating doses of radiation, MSCs lost their typical spindle-shaped morphology, their growth rate markedly decreased and eventually stopped (at P4-P6) by reaching early senescence. Irradiated and starved MSCs maintained their typical immune-phenotype, ability to differentiate into adipocytes/osteoblasts and to inhibit mitogen-induced T-cell proliferation. The study of the genetic profile of irradiated/ starved MSCs did not show any alteration. While the induction of supramaximal stress triggered production of ROS and activation of DNA damage response pathway via multiple mechanisms, our data indicate that irradiated/starved MSCs, although presenting altered morphology/growth rate, do not display increased propensity for malignant transformation

Advanced Electrocardiographic Predictors of Sudden Death in Familial Dysautonomia

To identify accurate predictors for the risk of sudden death in patients with familial dysautonomia (FD). Ten-minute resting high-fidelity 12-lead ECGs were obtained from 14 FD patients and 14 age/gender-matched healthy subjects. Multiple conventional and advanced ECG parameters were studied for their ability to predict sudden death in FD over a subsequent 4.5-year period, including multiple indices of linear and non-linear heart rate variability (HRV); QT variability; waveform complexity; high frequency QRS; and derived Frank-lead parameters. Four of the 14 FD patients died suddenly during the follow-up period, usually with concomitant pulmonary disorder. The presence of low vagally-mediated HRV was the ECG finding most predictive of sudden death. Concomitant left ventricular hypertrophy and other ECG abnormalities such as increased QTc and JTc intervals, spatial QRS-T angles, T-wave complexity, and QT variability were also present in FD patients, suggesting that structural heart disease is fairly common in FD. Although excessive or unopposed cardiac vagal (relative to sympathetic) activity has been postulated as a contributor to sudden death in FD, the presence of low vagally-mediated HRV was paradoxically the best predictor of sudden death. However, we suggest that low vagally-mediated HRV be construed not as a direct cause of sudden death in FD, but rather as an effect of concurrent pathological processes, especially hypoxia due to pulmonary disorders and sleep apnea, that themselves increase the risk of sudden death in FD and simultaneously diminish HRV. We speculate that adenosine may play a role in sudden death in FD, possibly independently of vagal activity, and that adenosine inhibitors such as theophylline might therefore be useful as prophylaxis in this disorder

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: a pooled analysis of 1018 population-based measurement studies with 88.6 million participants

Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1,018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean SBP, mean DBP and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probit-transformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-2016, at the same level of population mean SBP and DBP, men and women in south Asia and in central Asia, Middle East and north Africa would have the highest prevalence of raised blood pressure, and men and women in the high-income Asia Pacific and high-income western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups