Syndrome of inappropriate antidiuretic hormone secretion.
Hyponatremia is the most frequent electrolytic disorder in hospitalized patients, and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), the most frequent cause of hiponatremia with clinically normal extracellular volume. It consists of a disorder of the regulation of body water that obeys to different causes, mainly cancer, pulmonary illnesses, disorders of the central nervous system and diverse drugs. As in any hiponatremia it a physiological knowledge of the regulation of body water and sodium is essential as well as the application of precise diagnostic criteria in order to manage the problem with an effective treatment. The available data until the moment show that the clinical diagnosis of SIADH made by professionals is mainly not supported on the established criteria drawn by experts and this lack of accuracy probably hits in the therapeutic result. The basis of the treatment of the SIADH is to correct its cause, water restriction, solutes (sodium chloride) and the use of vaptans in case of failure of the previous measures.


An Evaluation of Applicability of Salivary Uric Acid Measurement in Preeclampsia and Normal Pregnancy and Its Correlation with Serum Uric Acid.
Hypertensive disorders complicate 5-10% of all pregnancies and contribute greatly to maternal morbidity and mortality. There are various biomarkers for detection of preeclampsia. Several studies have reported that positive correlation exists between serum uric acid (UA) levels and adverse maternal and fetal outcome. Significant advances have been made toward validation of salivary biomarkers. We conducted this study to determine levels of salivary UA and its correlation with serum UA normal pregnancy and preeclampsia. Present cross-sectional study was conducted in tertiary care teaching hospital in North India. One hundred and fifty participants were divided into control group (50 healthy non-pregnant females), study group I (50 normotensive pregnant females), study group II (50 pregnant females with preeclampsia), and both salivary and serum UA was estimated at the same time. Saliva UA of study group II (4.86 ± 2.37 mg/dl) was significantly higher (p < 0.001) than that of control group (2.09 ± 1.33 mg/dl) and study group I (3.32 ± 1.77 mg/dl). Serum UA of study group II (6.63 + 2.78 mg/dl) was significantly higher (p < 0.001) than that of control group (2.94 + 1.94 mg/dl) and also study group I (5.18 + 2.31 mg/dl) (p = 0.0006). UA is present in the saliva of women with preeclampsia and has linear correlation with serum UA. Therefore, salivary UA can be used in place of invasive serum UA to monitor women with preeclampsia. Saliva collection is easy, noninvasive and cost-effective. Salivary UA testing may be useful for monitoring preeclampsia at home-based and hospital setting.


Delayed Treatment of Bloodstream Infection at Admission is Associated With Initial Low Early Warning Score and Increased Mortality.
To identify factors associated with antibiotic treatment delay in patients admitted with bloodstream infections (BSIs). Retrospective cohort study. North Zealand Hospital, Denmark. Adult patients with positive blood cultures obtained within the first 48 hours of admission between January 1, 2015, and December 31, 2015 (n = 926). First recorded Early Warning Score (EWS), patient characteristics, time to antibiotic treatment, and survival at day 60 after admission were obtained from electronic health records and medicine module. Presence of contaminants and the match between the antibiotic treatment and susceptibility of the cultured microorganism were included in the analysis. Data were stratified according to EWS quartiles. Overall, time from admission to prescription of antibiotic treatment was 3.7 (3.4-4.0) hours, whereas time from admission to antibiotic treatment was 5.7 (5.4-6.1) hours. A gap between prescription and administration of antibiotic treatment was present across all EWS quartiles. Importantly, 23.4% of patients admitted with BSI presented with an initial EWS 0-1. Within this group of patients, time to antibiotic treatment was markedly higher among nonsurvivors at day 60 compared with survivors. Furthermore, time to antibiotic treatment later than 6 hours was associated with increased mortality at day 60. Among patients with an initial EWS of 0-1, 51.3% of survivors received antibiotic treatment within 6 hours, whereas only 19.0% of nonsurvivors received antibiotic treatment within 6 hours. Among patients with initial low EWS, delay in antibiotic treatment of BSIs was associated with increased mortality at day 60. Lag from prescription to administration may contribute to delayed antibiotic treatment. A more frequent reevaluation of patients with infections with a low initial EWS and reduction of time from prescription to administration may reduce the time to antibiotic treatment, thus potentially improving survival.


Primary cultures of bovine chromaffin cells synthesize and secrete vasoactive intestinal polypeptide (VIP).
Dispersed cells of the bovine adrenal medulla express immunoreactive vasoactive intestinal polypeptide (VIP) after 24 hours in culture, although VIP could not be detected in extracts of bovine adrenal medulla or cortex. Immunoreactive VIP eluted from a reversed-phrase chromatography column with the same retention time as authentic porcine VIP1-28. VIP in chromaffin cells in culture appears to be contained in a secretory granule pool, since it, like methionine-enkephalin (met-enk) was released into the medium after exposure of cells to nicotine, carbachol, veratridine and elevated potassium in a dose-dependent manner. Dose-response curves for VIP and enkephalin release by the above secretagogues were similar but not identical. Enkephalins and VIP may either be contained in separate subpopulations of chromaffin cells or co-stored in the same cells.


Prevalence of ovarian cancer among women with a CA125 level of 35 U/ml or less.
The optimal upper limit of the normal range for CA125 in ovarian cancer screening is unknown. We investigated the prevalence of ovarian cancer among women in the Shizuoka Cohort Study on Ovarian Cancer Screening (SCSOCS) trial who had an abnormal ultrasound (US) and a CA125 level of 35 U/ml or less. Of 48,027 women enrolled in the SCSOCS trial, 40,801 women never had a CA125 level of more than 35 U/ml, and underwent transvaginal US. Among the 40,801 women (age range 45-85 years), 4,859 women had an abnormal transvaginal US examination (category 1 [simple morphology], 4,741 women, and category 2 [complex morphology], 118 women). Of the 4,859 women, 981 (912 with the category 1 and 69 with the category 2) had a surgery. Of the 981 women, ovarian cancer was diagnosed in 8 (0.815%), and 5 of these 8 cancers (63%) were in stage I. The prevalence of ovarian cancer with abnormal US was 0.207% among women with a CA125 level of up to 15 U/ml, 0.488% among those with values of 15-20 U/ml, 0.685% among those with values of 20-25 U/ml, 2.04% among those with values of 25-30 U/ml, and 6.12% among those with values of 30-35 U/ml. Surgery-detected ovarian cancer is not rare among women with CA125 levels of 35 U/ml or less - levels generally thought to be in the normal range.


Upregulation of the hyperpolarization-activated current increases pacemaker activity of the sinoatrial node and heart rate during pregnancy in mice.
Pregnancy is associated with a faster heart rate (HR), which is a risk factor for arrhythmias. However, the underlying mechanisms for this increased HR are poorly understood. Therefore, this study was performed to gain mechanistic insight into the pregnancy-induced increase in HR. Using surface ECG we observed that pregnant (P) mice have faster HR (531±14 beats per minute [bpm]) compared with nonpregnant (NP) mice (470±27 bpm; P<0.03). Results obtained with Langendorff-perfused hearts showed that this difference persisted in the absence of autonomic nervous innervation (NP, 327±16 bpm; P, 385±18 bpm; P<0.02). Spontaneous action potentials of sinoatrial node cells from pregnant mice exhibited higher automaticity (NP, 292±13 bpm; P, 330±12 bpm; P=0.047) and steeper diastolic depolarization (NP, 0.20±0.03 V/s; P, 0.40±0.06 V/s; P=0.004). Pregnancy increased the density of the hyperpolarization-activated current (If) (at -90mV: NP, -15.2±1.0 pA/pF; P, -28.6±2.9 pA/pF; P=0.0002) in sinoatrial node cells. Voltage dependence of the If activation curve and the intracellular cAMP levels were unchanged in sinoatrial node cells of pregnant mice. However, there was a significant increase in HCN2 channel protein expression with no change in HCN4 expression. Maximal depolarizing shift of the If activation curve induced by isoproterenol was attenuated in pregnancy. This reduced response to isoproterenol may be attributable to the lower cAMP sensitivity of HCN2 isoform compared with that of HCN4. This study shows that an increase in If current density contributes to the acceleration of sinoatrial node automaticity and explains, in part, the higher HR observed in pregnancy.


Two unresolved problems facing models of the Self-Nonself discrimination.
Although the Associative (linked) Recognition of Antigen (ARA) model for a Self (S)-Nonself (NS) discrimination, now over 50 years old, is built on a solid conceptual and experimental base, two unsettled questions remain. In examining these questions, unanticipated aspects of the ARA Model itself had to be reconsidered. This essay spells out these problems and suggests possible solutions.


Congenital Trismus From Brainstem Dysgenesis: Case Report and Review of Literature.
Trismus refers to any condition inducing limited mouth opening and may present as a result of acquired or congenital pathology. We present the case of a newborn who presented with severe, congenital trismus due to brainstem dysgenesis. We describe the course of his investigations, and a multidisciplinary approach to the management of his care and follow-up. To our knowledge, this is one of the earliest reported cases of congenital trismus attributable to brainstem dysgenesis. A literature review was conducted to provide an overview of the differential pathogenesis as it presents in congenital cases and discuss the complexity of managing congenital trismus due to brainstem dysgenesis in a neonate and infant.


The rise of western rationalism: Paul Feyerabend's story.
I summarize certain aspects of Paul Feyerabend's account of the development of Western rationalism, show the ways in which that account is supposed to run up against an alternative, that of Karl Popper, and then try to give a preliminary comparison of the two. My interest is primarily in whether what Feyerabend called his 'story' constitutes a possible history of our epistemic concepts and their trajectory. I express some grave reservations about that story, and about Feyerabend's framework, finding Popper's views less problematic here. However, I also suggest that one important aspect of Feyerabend's material, his treatment of religious belief, can be given an interpretation which makes it tenable, and perhaps preferable to a Popperian approach.


Effect of common storage temperatures and container types on urine protein : creatinine ratios in urine samples of proteinuric dogs.
Preanalytic protein adsorption to polymer and glass container surfaces may decrease urine protein concentration measurements and urine protein: creatinine ratios (UPC). Urine stored in PC or glass containers will have lower UPC than urine stored in HP containers. The specific objective was to determine whether clinically relevant differences in UPC would be detected after storage in glass, PC, or HP containers using common storage times and temperatures. Twelve client-owned dogs with proteinuria. Prospective, nonmasked study, divided into 2 phases. The first phase was a pilot study involving multiple (n = 5) measurements at each storage condition using 24-hours urine samples from 2 dogs with persistent renal proteinuria of different magnitude. The second phase used urine samples from 10 dogs with proteinuria of variable magnitude. Sample aliquots were stored in HP, PC, and glass containers at 24°C for 4 hours, 4°C for 12 hours, and -20°C for 72 hours. The UPC of each was measured after storage and compared with baseline. Statistically significant but clinically irrelevant differences were found in phase 1. In phase 2, storage conditions did not affect urinary protein or creatinine concentrations or UPC. Collection and storage of canine urine samples in clean HP, PC, or glass containers at 24°C for 4 hours, 4°C for 12 hours, or -20°C for 72 hours is unlikely to result in clinically relevant decreases in measured UPC values.


A gold nanocluster-based sensor for sensitive uric acid detection.
In this report, we developed a highly sensitive and selective sensor for the detection of uric acid. Gold nanoclusters were synthesized with bovine serum albumin as the template material. Under the catalysis of urate oxidase, hydrogen peroxide was generated, which quenched the fluorescence from the gold nanoclusters. Furthermore, excessive iodide was found capable of enhancing this quenching effect, which significantly improved the sensitivity of the detection. Under an optimized condition, the extent of quenching was found linearly related to uric acid concentration in the range of 0.7-80 μM, and uric acid as low as 120 nM could be detected. With simple dilutions, blood samples could be analyzed, and satisfactory recoveries were obtained.


[Type B natriuretic peptide in the diagnosis of heart failure with preserved systolic function].
Heart failure (HF) with preserved left ventricular systolic function (LVSF) is observed in up to 50% patients with HF. There is no consensus on non-invasive diagnosis of this entity. Evaluation of B-type natriuretic peptide (BNP) in the diagnosis of HF with preserved left ventricular systolic function. Prospective study. One hundred and seventy-six consecutive patients with suspected HF were evaluated. Patients were classified as having HF with preserved LVSF, if they had symptoms and signs of HF, an ejection fraction greater than 40% and an abnormal Doppler pattern of the mitral inflow or atrial fibrilation and no other causes for the symptoms. All patients had a 12-lead EKG, chest roentgenogram, simple spirometry, M-mode and 2D echocardiogram with pulsed Doppler study of transmitral inflow and determination of plasma BNP levels. Of the 176 patients, 65 had ejection fraction greater than 40%. Of these patients 46 were classified as having HF with preserved LVSF and 19 as not having HF. Patients with HF and preserved LVSF were older, had a higher systolic blood pressure (SBP), less pathologic Q waves on ECG and higher left ventricular ejection fraction and plasma BNP than patients without HF. Multivariate analysis revealed that BNP and SBP were independently associated with the diagnosis of HF. The accuracy of BNP in the diagnosis of HF with preserved LVSF evaluated by the area under the receiver operating characteristic curve was 0.94. These results suggest that the measurement of BNP levels can help clinicians in the diagnosis of HF with preserved LVSF. Whether BNP levels might be used in clinical practice as a test for the diagnosis of HF with preserved LVSF is a question that merits further studies.


Controlled endoscopic retrieval of ectopic ureteral catheters using fluoroscopic guidance.
The double-J ureteral catheter has been popularized as an ideal internal ureteral stent. Migration of the distal end of the catheter up the ureter, however, can complicate its safe removal. A safe, controlled method of stent extraction is described using a C-arm fluoroscopic unit.


A model for systematic child protective service training.
A model training program structured to provide basic knowledge and skills for child protective workers appears to be meeting its objectives.


Auto-Augmentation Mastopexy: Inferiorly Based Parenchymal Flap Technique and Evaluation of Outcomes Using BREAST-Q After 151 Consecutive Patients.
Mastopexy is one of the most performed annual plastic surgery procedures; hence, various techniques are described over the last decades. It varies from simple skin incisions to internally shaped pedicle designs. In this study, the authors present their modified auto-augmentation mastopexy technique and the resulting patient satisfaction. For this retrospectively conducted study, 151 female patients were included. The average age was 40.6 years (range, 27-72 years). All patients underwent auto-augmentation mastopexy which is a combination of a superior pedicle for the nipple-areola complex and an inferiorly based soft-tissue flap which is shaped like an implant. Additionally, the BREAST-Q for Reduction/Mastopexy was used to analyze patient-reported satisfaction and quality of life after mastopexy. All breast corrections were successfully performed. General complication rate was 9%, and no major complication was observed. In two patients, local surgical revision due to hypertrophic scarring and nipple asymmetry was necessary. Analysed surveys of the BREAST-Q showed statistically significantly improved results. Depending on the breast-shape and the grade of ptosis, the selection of mastopexy technique is crucial. Our described mastopexy procedure is a safe and easily reproducible technique for almost all shapes of ptotic breasts which fulfill patient desires as well as aesthetic satisfaction and quality of life. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.


[The effects of hypnosis by virtual reality on tolerance to flexible bronchoscopy].
Patients often perceive flexible bronchoscopy as an unpleasant procedure. The aim of this study was to investigate the effect of virtual reality (VR) hypnosis on tolerance to flexible bronchoscopy. We conducted a prospective, randomized, controlled, monocentric study comparing flexible bronchoscopy with VR-induced hypnosis to the usual procedure. Patient tolerance was evaluated using a visual analogue scale (VAS), the state-trait anxiety inventory (STAI) before and after the procedure and, finally, willingness to repeat the examination under the same conditions (WTR). Among the 70 patients included, 34 were randomized to the VR hypnosis group and 36 to the control group. There was no difference between the 2 groups in terms of modification of the pre-/post-bronchoscopy VAS for anxiety, pain, cough, choking, nausea and overall discomfort, or modification of the STAI score and WTR. Subgroup analysis among patients who were more anxious before the procedure revealed a trend toward reduced anxiety in the VR hypnosis group. This study did not observe any effect of VR hypnosis on the tolerance of patients during routine flexible bronchoscopy. However, VR hypnosis may be beneficial in patients with higher anxiety score before bronchoscopy, a hypothesis that needs to be confirmed by further studies with a larger number of subjects.


The Effects of Asthma and Bullying on Suicidal Behaviors Among US Adolescents.
Positive associations between suicidal behaviors and asthma have been established in previous adolescent studies. Few studies consider social risk factors, such as bullying. This study involved an analysis of suicidal behaviors and asthma, but also includes an assessment of whether these relationships were modified by the co-occurrence of bullying. Data included 13,154 participants from the 2013 Youth Risk Behavior Survey (YRBS), collected by the US Centers for Disease Control and Prevention. Logistic regression models were constructed and summarized using odds ratios (ORs) and 95% confidence intervals (95% CIs). When comparing adolescents with asthma who were bullied at school to those who were not bullied at school, the odds of contemplating suicide were increased by nearly 2-fold (OR = 1.8, 95% CI = 1.5-2.3), and the odds of creating a suicide plan were 2.3 times higher (OR = 2.3, 95% CI = 1.7-3.1). The odds of a suicide attempt and incurring an injury from a suicide attempt were also substantially increased. Similarly, increased odds of suicidal behaviors were observed for adolescents with asthma who were bullied electronically. Having asthma and being bullied are both associated with increased odds of suicidal behaviors.


Pen injury: a rare complication.
An 18-month-old male sustained an intra-oral injury after falling on a pen. The internal carotid artery was occluded without evident neurologic deficit. The pen tip was surgically removed from the cerebellum.


Reactivity of alkynylzirconates towards allyl bromides: selective formation of β-allyl-zirconacyclopentadienes.
Reaction of alkynylzirconates with allyl bromides afforded β-allyl-zirconacyclopentadienes with high selectivity in unique reaction site.


Left Atrial Strain Is the Best Predictor of Adverse Cardiovascular Outcomes in Patients with Chronic Kidney Disease.
Patients with chronic kidney disease (CKD) are at increased risk of adverse cardiovascular events, which is underestimated by traditional risk stratification algorithms. We sought to determine clinical and echocardiographic predictors of adverse outcomes in CKD patients. Two hundred forty-three prospectively recruited stage 3/4 CKD patients (male, 63%; mean age, 59.2 ± 14.4 years) without previous cardiac disease made up the study cohort. All participants underwent a transthoracic echocardiogram, with left ventricular (LV) and left atrial (LA) strain analysis. Participants were followed for 3.9 ± 2.7 years for the primary end point of cardiovascular death and major adverse cardiovascular event (MACE). The secondary end point was the composite of all-cause death and MACE. Fifty-four patients met the primary end point, and 65 the secondary end point. On log-rank tests, older age, diabetes mellitus, anemia, greater LV mass, reduced LV global longitudinal strain, larger indexed LA volume, higher E/e' ratio, and reduced LA reservoir strain (LASr; P < .01 for all) were independent predictors of cardiovascular death and MACE. On multivariable regression analysis of univariate predictors, LASr (P < .01) was the only independent predictor for the primary end point as well as for the secondary end point. Receiver operating characteristic curve analysis showed LASr was a stronger predictor of adverse events (area under the curve [AUC] = 0.84) compared to the Framingham (AUC = 0.58) and Atherosclerotic Cardiovascular Disease (AUC = 0.59) risk scores. LASr is an independent predictor of cardiovascular death and MACE in CKD patients, superior to clinical risk scores, LV parameters, and LA volume.


Comparison of the effects of 2-chloropropionate and dichloroacetate on ketogenesis and lipogenesis in isolated rat hepatocytes.
The respective effects of 2-chloropropionate and dichloroacetate on the pyruvate metabolic crossroads, lipogenesis and ketogenesis, were compared in hepatocytes isolated from fed rats. 2-Chloropropionate acts as an exclusive pyruvate dehydrogenase activator: it increases ketogenesis, lipogenesis, Krebs cycle intermediates and mitochondrial NADH/NAD+ ratio. The effects of dichloroacetate depend on experimental conditions and the intensity of its catabolization into oxalate: the resultant action of dichloroacetate on tested parameters combines the effects of pyruvate dehydrogenase activation on the one hand, and pyruvate carboxylase inhibition by oxalate on the other. A mixture of 2-chloropropionate plus oxalate mimics the effects of dichloroacetate. In hepatocytes from fed rats, endogenous lipogenesis is correlated with the mitochondrial NADH/NAD+ ratio, irrespective of the effector added.


The O-acylation of ketone enolates by allyl 1H-imidazole-1-carboxylate mediated with boron trifluoride etherate: a convenient procedure for the synthesis of substituted allyl enol carbonates.
A convenient access to substituted allyl enol carbonates was established through the reaction of ketone enolates with the complex of allyl 1H-imidazole-1-carboxylates and boron trifluoride etherate.


Whole gel processing procedure for GeLC-MS/MS based proteomics.
SDS-PAGE followed by in-gel digestion (IGD) is a popular workflow in mass spectrometry-based proteomics. In GeLC-MS/MS, a protein lysate of a biological sample is separated by SDS-PAGE and each gel lane is sliced in 5-20 slices which, after IGD, are analyzed by LC-MS/MS. The database search results for all slices of a biological sample are combined yielding global protein identification and quantification for each sample. In large scale GeLC-MS/MS experiments the manual processing steps including washing, reduction and alkylation become a bottleneck. Here we introduce the whole gel (WG) procedure where, prior to gel slice cutting, the processing steps are carried out on the whole gel. In two independent experiments human HCT116 cell lysate and mouse tumor tissue lysate were separated by 1D SDS PAGE. In a back to back comparison of the IGD procedure and the WG procedure, both protein identification (>80% overlap) and label-free protein quantitation (R2=0.94) are highly similar between procedures. Triplicate analysis of the WG procedure of both HCT116 cell lysate and formalin-fixed paraffin embedded (FFPE) tumor tissue showed identification reproducibility of >88% with a CV<20% on protein quantitation. The whole gel procedure allows for reproducible large-scale differential GeLC-MS/MS experiments, without a prohibitive amount of manual processing and with similar performance as conventional in-gel digestion. This procedure will especially enable clinical proteomics for which GeLC-MS/MS is a popular workflow and sample numbers are relatively high.


Germinal-center organization and cellular dynamics.
Germinal centers (GCs) are important sites of antibody affinity maturation. In the classical model, the GC dark zone contains large centroblasts that are rapidly proliferating and undergoing somatic hypermutation of their antibody variable-region genes. Centroblasts give rise to smaller nonproliferating centrocytes in the light zone that compete for binding antigen on follicular dendritic cells. Recently, the approach of real-time imaging of GCs by two-photon microscopy of intact lymph nodes has provided new insights into GC dynamics that both support and challenge fundamental aspects of this model. Here we review recent and older findings on cell migration, proliferation, and interaction dynamics in the GC and discuss a model in which dark- and light-zone cells are morphologically similar, proliferation occurs in both zones, and GC B cells compete for T cell help as well as antigen.


Waist to height ratio in nonalcoholic fatty liver disease - Systematic review and meta-analysis.
Current nonalcoholic fatty liver disease (NAFLD) guidelines do not provide any recommendations regarding the waist-to-height ratio (WHtR), a simple obesity metric calculated by dividing waist circumference by height. Therefore, we performed a systematic review and meta-analysis aiming to evaluate WHtR in NAFLD. We performed a systematic electronic search on PubMed, Embase, and Scopus, identifying observational studies assessing WHtR in NAFLD. QUADAS-2 tool was used to evaluate the quality of included studies. The two main statistical outcomes were the area under the curve (AUC) and the mean difference (MD). We included a total of 27 studies in our quantitative and qualitative synthesis, with a total population of 93,536 individuals. WHtR was significantly higher in NAFLD patients compared to controls with an MD of 0.073 (95% CI 0.058 - 0.088). This was also confirmed after conducting a subgroup analysis according to the hepatic steatosis diagnosis method, for ultrasound (MD 0.066 [96% CI 0.051 - 0.081]) and transient elastography (MD 0.074 [96% CI 0.053 - 0.094]). Moreover, NAFLD male patients presented significantly lower WHtR compared to female patients (MD -0.022 [95% CI -0.041 - -0.004]). The AUC of WHtR for predicting NAFLD was 0.815 (95% CI 0.780 - 0.849). WHtR is considerably higher in NAFLD patients compared to controls. Female NAFLD patients present higher WHtR compared to NAFLD male patients. In comparison to other presently suggested scores and markers, the WHtR's accuracy in predicting NAFLD is considered acceptable.


The application of 13C NMR to the characterization of phospholipid metabolism in cells.
31P and 13C NMR spectroscopy of lipid extracts of T47D human breast cancer spheroids and the use of 13C-labeled lipid precursors [3-13C]serine,[1,2-13C]ethanolamine, and [1,2-13C]choline enabled us to determine the rate of 13C incorporation into the major phospholipids and to show that the synthesis of phosphatidylethanolamine in T47D cells is via both the CDP-ethanolamine pathway and serine decarboxylation, with the extent of each depending on the concentration of ethanolamine in the medium. In the presence of low ethanolamine (3.4 microM), both pathways contribute in equal proportions, while in the presence of high ethanolamine, the CDP-ethanolamine pathway predominates.


Desmin filaments are stably associated with the outer nuclear surface in chick myoblasts.
Eukaryotic cells have highly organized, interconnected intracellular compartments. The nuclear surface and cytoplasmic cytoskeletal filaments represent compartments involved in such an association. Intermediate filaments are the major cytoskeletal elements in this association. Desmin is a muscle-specific structural protein and one of the earliest known muscle-specific genes to be expressed during cardiac and skeletal muscle development. Desmin filaments have been shown to be associated with the nuclear surface in the myogenic cell line C2C12. Previous studies have revealed that mice lacking desmin develop imperfect muscle, exhibiting the loss of nuclear shape and positioning. In the present work, we have analyzed the association between desmin filaments and the outer nuclear surface in nuclei isolated from pectoral skeletal muscle of chick embryos and in primary chick myogenic cell cultures by using immunofluorescence microscopy, negative staining, immunogold, and transmission electron microscopy. We show that desmin filaments remain firmly attached to the outer nuclear surface after the isolation of nuclei. Furthermore, positive localization of desmin persists after gentle washing of the nuclei with high ionic strength solutions. These data suggest that desmin intermediate filaments are stably and firmly connected to the outer nuclear surface in skeletal muscles cells in vivo and in vitro.


32-channel wide-bandwidth massive RF photonic combiner based on distributed groups of arrayed photodetectors.
We propose and experimentally demonstrate a low-loss, radio frequency (RF) photonic signal combiner with flat response from 1 GHz to 15 GHz and low group delay variation of 9 ps. The distributed group array photodetector combiner (GAPC) is implemented in a scalable Si photonics platform and has applications in RF photonic systems that rely on combining massive numbers of photonic signals.


Intraneural lipofibroma of the median nerve.
A case of an intraneural lipofibroma of the median nerve is described. The patient was first seen with an enlarging mass on the flexor side of the wrist and in the palm. After interfascicular dissection of the tumor there was a permanent loss in sensibility and motor function. In most cases decompression of the nerve will suffice; resection by means of interfascicular dissection is rarely justified.


Indications and Outcomes for Non-Trauma Emergency Laparotomy: A Comparison of Rwanda, South Africa, and the USA.
Emergency conditions requiring exploratory laparotomy (EL) can be challenging. The objective of this study is to describe indications, outcomes, and risk factors for perioperative mortality (POMR) after non-trauma EL. This was a prospective study of patients undergoing non-trauma EL at four hospitals in Rwanda, South Africa, and the USA. Multivariate logistic regression was used to determine factors associated with POMR. Over one year, there were 632 EL with the most common indications appendicitis (n = 133, 21%), peptic ulcer disease (PUD) (n = 101, 16%), and hernia (n = 74, 12%). In Rwanda, the most common indications were appendicitis (n = 41, 19%) and hernia (n = 37, 17%); in South Africa appendicitis (n = 91, 28%) and PUD (n = 60, 19%); and in the USA, PUD (n = 16, 19%) and adhesions from small bowel obstruction (n = 16, 19%). POMR was 11%, with no difference between countries (Rwanda 7%, South Africa 12%, US 16%, p = 0.173). Risk factors associated with increased odds of POMR included typhoid intestinal perforation (adjusted odds ratio (aOR): 16.48; 95% confidence interval (CI): 4.31, 62.98; p value < 0.001), mesenteric ischemia (aOR: 13.77, 95% CI: 4.21, 45.08, p value < 0.001), cancer (aOR: 5.84, 95% CI: 2.43, 14.05, p value < 0.001), other diagnoses (aOR: 3.97, 95% CI: 3.03, 5.20, p value < 0.001), high ASA score (score ≥ 3) (aOR: 3.95, 95% CI: 3.03, 5.15, p value < 0.001), peptic ulcer disease (aOR: 2.82, 95% CI: 1.64, 4.85, p value < 0.001), age > 60 years (aOR: 2.32, 95% CI: 1.41, 3.83, p value = 0.001), and ICU admission (aOR: 2.23, 95% CI: 1.24, 3.99, p value = 0.007). Surgery in the US was associated with decreased odds of POMR (aOR: 0.41, 95% CI: 0.21, 0.80, p value = 0.009). Indications for EL vary between countries and POMR is high. Differences in mortality were associated with patient and disease characteristics with certain diagnoses associated with increased risk of mortality. Understanding the risk factors and outcomes for patients with EL can assist providers in judicious patient selection, both for patient counselling and resource allocation.


2,7-dimethyl-3,8-dinitrodipyrazolo[1,5-a:1',5'-d]pyrazine-4,9-dione: a new labelling reagent for liquid chromatographic analysis of amino acids.
The use of 2,7-dimethyl-3,8-dinitrodipyrazolo[1,5-a:1',5'-d]pyrazine-4,9-dione as pre-column reagent for LC analysis of amino acids is proposed. The compound reacts (30 min at 68 degrees C in presence of 0.04 M triethylamine in a dimethylsulfoxide-water mixture) with primary and secondary amino function and the stable resulting adducts can be chromatographed under reversed-phase conditions and detected at lambda=280 nm. The derivatization conditions were optimized by a series of experiments. The effect of temperature, triethylamine concentration and reagent on the reaction was investigated. The yield of the glycine derivative was found to be quantitative at a reagent amino acid molar ratio of about 6 by comparison with an authentic specimen of synthesized glycine adduct. Application of the method to quality control of commercially available oral polyaminoacid formulations is described.


Food security during infancy: implications for attachment and mental proficiency in toddlerhood.
This study examined the associations between household food security (access to sufficient, safe, and nutritious food) during infancy and attachment and mental proficiency in toddlerhood. Data from a longitudinal nationally representative sample of infants and toddlers (n = 8944) from the Early Childhood Longitudinal Study-9-month (2001-2002) and 24-month (2003-2004) surveys were used. Structural equation modeling was used to examine the direct and indirect associations between food insecurity at 9 months, and attachment and mental proficiency at 24 months. Food insecurity worked indirectly through depression and parenting practices to influence security of attachment and mental proficiency in toddlerhood. Social policies that address the adequacy and predictability of food supplies in families with infants have the potential to affect parental depression and parenting behavior, and thereby attachment and cognitive development at very early ages.


Safer Sex Communication and Sexual Health Behaviors Among a Representative Statewide Sample of Homeless Adolescents.
Homeless adolescents are at substantial risk of human immunodeficiency virus (HIV), other sexually transmitted infections (STIs), and unplanned pregnancy; however, little research has assessed factors, such as safer sex communication, that may protect homeless adolescents against these negative outcomes. Using the 2015 North Carolina Youth Risk Behavior Survey (YRBS; unweighted N = 5,486; ages 12 to 18; 5% homeless), we compared homeless adolescents' primary safer sex communication sources (i.e., health care providers, parents, teachers, peers, religious leaders) to housed adolescents' communication sources and assessed how these sources relate to sexual health behaviors, including condom use, HIV testing, and number of sexual partners. Most homeless adolescents (61%), and 46% of housed adolescents reported having questions about sex. Further, twice as many homeless adolescents communicated primarily with health care providers compared to housed adolescents. Importantly, among homeless adolescents, communicating primarily with health care providers or teachers was related to greater likelihood of condom use and communicating primarily with religious leaders was related to greater likelihood of HIV testing. Parent communication was unrelated to homeless adolescents' sexual health behaviors. Last, communicating primarily with peers was associated with reduced likelihood of HIV testing. Having nonparental adult communication sources, including health care providers, teachers, and religious leaders, may be critical for encouraging safer sex behaviors among homeless adolescents.


Pharmacokinetics and biotransformation of the prostacyclin analogue, ZK 36 374, in the beagle dog.
Tritium-labelled ZK 36 374 was administered to three female beagle dogs intravenously and orally in a dose of 200 micrograms/kg. Blood and plasma levels and excretion with urine and feces of drug and metabolites were measured. ZK 36 374 was rapidly absorbed. The bioavailability was estimated as about 10% of the dose. The concentration of radio-labelled compounds in the plasma declined in three phases with half-lives of 3 min, 46 min and approx. 2 d. The half-life of the unchanged drug was 14 min. ZK 36 374 was totally metabolized and excreted mainly via the kidneys.


Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils.
Decreased cerebral blood flow causes cognitive impairments and neuronal injury in vascular dementia. In the present study, we reported that donepezil, a cholinesterase inhibitor, improved transient global cerebral ischemia-induced spatial memory impairment in gerbils. Treatment with 5mg/kg of donepezil for 21 consecutive days following a 10-min period of ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 region. In Morris water maze test, memory impairment was significantly improved by donepezil treatment. Western blot analysis showed that donepezil treatment prevented reductions in p-CaMKII and p-CREB protein levels in the hippocampus. These results suggest that donepezil attenuates the memory deficit induced by transient global cerebral ischemia and this neuroprotection may be associated with the phosphorylation of CaMKII and CERB in the hippocampus.


Nitric oxide-dependent osteopontin expression induces metastatic behavior in HepG2 cells.
Our objective was to delineate the role of nitric oxide (NO) in osteopontin (OPN)-associated metastatic properties in HepG2 cells. OPN is the major phosphoprotein secreted by malignant cells in patients with advanced metastatic cancer, is frequently overexpressed in human tumors, and has been implicated as a key mediator of tumor cell metastasis. OPN is significantly overexpressed in hepatocellular cancer (HCC) and correlates with capsular infiltration and behavior. In addition, significantly increased inducible nitric oxide synthase (iNOS) and NO expression are found in HCC. In archived human samples of normal, cirrhotic, and HCC livers, we demonstrate that iNOS and OPN protein are strongly coexpressed in hepatoma cells. In the setting of cirrhosis, hepatocytes express iNOS, but not OPN. Further in vitro studies performed with HepG2 hepatocellular cancer cells demonstrate that exogenous NO transcriptionally upregulates OPN expression. Enhanced expression of OPN in this setting is associated with increased in vitro cell adhesion and invasion. These data suggest that NO enhances HCC expression of OPN and, as a result, conveys a metastatic phenotype.


Olopatadine hydrochloride suppresses hot flashes induced by topical treatment with tacrolimus ointment in rats.
Tacrolimus ointment is prescribed for patients with atopic dermatitis, although it is known to cause transient burning sensations and hot flashes in the applied skin. The aim of this study was to evaluate the effects of olopatadine hydrochloride (olopatadine), an antiallergic agent with a histamine H1 receptor (H1R) antagonistic activity, on the incidence of hot flashes induced by topical treatment with tacrolimus ointment in rats. Consequently, the skin temperature was increased by the topical application of tacrolimus ointment in rats, and the rise in skin temperature was inhibited by pretreatment with olopatadine in a dose-dependent manner. Inhibitory effect of olopatadine on tacrolimus-induced skin temperature elevation was significantly more potent than that of cetirizine hydrochloride, other antiallergic agent with H1R antagonistic activity, at doses in which both agents exhibit comparable H1R antagonistic activity in rats. These results suggest that H1R antagonistic activity-independent mechanism contribute to the inhibitory effect of olopatadine on tacrolimus-induced skin temperature elevation. Olopatadine also significantly inhibited increases in vascular permeability and nerve growth factor production in the skin induced by topical tacrolimus treatment. Thus, the onset of hot flashes in rats is quantitatively determined by measuring the skin temperature and olopatadine attenuates hot flashes induced by topical tacrolimus ointment in rats, suggesting that the combination application with olopatadine and tacrolimus ointment is useful for improving medication adherence with tacrolimus ointment treatment in patients with atopic dermatitis.


[Effectiveness of the new Soviet immunomodulator mielopid in the combined treatment of patients with chronic pyoderma].
Thirty-four patients with chronic pyoderma have been examined. Fifteen of these have been treated with mielopid (18 mg per course). Immunologic and clinical examinations carried out in 3-10 months after therapy have demonstrated a wide-spectrum immunostimulating action of the new drug.


Two types of electronic EPSP evoked in amphibian motoneurons by ventral root stimulation.
Motoneurons of hemisected perfused frog spinal cord were used for intracellular recording of EPSP produced by ventral root stimulation. Two varieties of electrotonic VR-EPSP resistant to Ca-lack and to addition of 10 mM Mg2+ and 2 mM Mn2+ have been encountered. The early VR-EPSP started before the full somadendritic invasion and the time constant of their decay varied between 11 and 25 msec, mean 15.4 +/- 1.8 msec, i.e., it was significantly longer than the time constant of the motoneuronal membrane (2.6--6.9 msec, mean 4.4 +/- 0.5 msec). The late VR-EPSPs appeared after a latent period which was significantly longer than that of an antidromic spike. They started after the full somadendritic invasion and had very rapid time course, the time constant of their decay approximated that of the motoneuronal membrane. The shape of the late VR-EPSP both before and after treatment with 4-AP of TEA which markedly facilitated its appearance resembled the shape of an antidromic spike, whereas this correlation was not found in the case of the early VR-EPSP. When the temperature was elevated above 18--19 degree C the late VR-EPSPs disappeared but the early VR-EPSPs still could be recorded. The available evidence suggests that the early VR-EPSPs are produced by direct synaptic interconnections between motoneurons and recurrent collaterals of the motor axons, and the VR-EPSPs are transmitted across dendrodendritic junctions.


Polyaniline Nanofibers-Embedded Gold Nanoparticles Obtained by Template-Free Procedure with Immobilization Prospects.
In this work, template-free nanostructured conducting polymers (nCPs)-embedded gold nanoparticles (AuNPs) from aniline, thiophene and 3,4-ethylenedioxythiophene have been prepared via a one-pot sonochemical method. The synthesis of the nanocomposite (nCPs-AuNPs) was achieved in a short period of time (5-10 min), by applying high-energy ultrasound to an aqueous mixture of a CP precursor monomer and KAuCl4, in the presence of LiClO4 as dopant. The synthesis process is simpler, greener and faster in comparison to other procedures reported in the literature. Remarkably, bulk quantities of doped polyaniline PANI-AuNPs nanofibers were obtained. Subsequently, they were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDS) and Fourier transform infrared spectroscopy (FTIR), as well as by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). PANI-AuNPs nanofibers were also employed as immobilization matrix for a benchmark enzyme, glucose oxidase (GOX). Finally, glucose was determined in real samples of white and red wines by using the so-obtained GOX-PANI-AuNPs/Sonogel-Carbon biosensor, providing outstanding recoveries (99.54%). This work may offer important insights into the synthesis of nanostructured conducting polymers and also stimulates the exploration of the applications of these nanocomposites, especially in research fields such as (bio)sensors, catalysis and composite materials.


Can 68Ga-PSMA-11 Positron Emission Tomography/Computerized Tomography Predict Pathological Response of Primary Prostate Cancer to Neoadjuvant Androgen Deprivation Therapy? A Pilot Study.
We explored the role of 68Ga-PSMA-11 positron emission/computerized tomography as a predictor of pathological response to neoadjuvant androgen deprivation therapy combined with abiraterone for high risk prostate cancer. A total of 45 patients with localized high risk prostate cancer who had serial 68Ga-PSMA-11 positron emission tomography/computerized tomography scans before and after 6 months of androgen deprivation therapy plus abiraterone neoadjuvant treatment followed by radical prostatectomy were included in this study. Complete pathological response or minimal residual disease <5 mm on whole mount histopathology was defined as favorable pathological response. The diagnostic performance of prostate specific antigen response and positron emission tomography/computerized tomography response for favorable pathological response was calculated. Univariable and multivariable logistic regression analyses of clinical and imaging variables were also performed to identify favorable pathological response. Compared to the prostate specific antigen response, positron emission tomography/computerized tomography response had a significantly higher specificity in diagnosing favorable pathological response (89.7% vs 62.1%, p=0.043). Preoperative nadir prostate specific antigen (OR 0.121, 95% CI 0.028-0.529, p=0.005), posttreatment maximum standardized uptake value (OR 7.072, 95% CI 2.035-24.579, p=0.002) and posttreatment tumor volume (OR 7.896, 95% CI 1.415-44.054, p=0.018) measured on positron emission tomography/computerized tomography were significantly associated with favorable pathological response in univariable logistic regression analysis. On multivariable logistic regression analysis, only posttreatment maximum standardized uptake value was found to be an independent predictor of favorable pathological response (OR 9.69, 95% CI 1.439-65.242, p=0.020). 68Ga-PSMA positron emission tomography/computerized tomography has a better diagnostic performance of pathological response to neoadjuvant treatment compared with prostate specific antigen, with maximum standardized uptake value being an independent predictive factor. This pilot study suggests that prostate specific membrane antigen positron emission tomography/computerized tomography may serve as a potential predictor of pathological response to neoadjuvant treatment.


[Quality of life in patients with choroidal melanoma].
To determine whether iodine 125 brachytherapy or enucleation is better for quality of life in patients treated for choroidal melanoma. Sixty-five patients with choroidal melanoma were treated with a modified version of VF-14 iodine 125 brachytherapy, enucleation or both. Results of this treatment were then statistically analyzed. Statistically significant differences were found between visual acuity in the affected eye and binocular vision (initial and final), with an important decline after the treatment. The global medial score in the VF questionnaire decreased in a statistically significant manner after the treatment. We can confirm that patients treated with brachytherapy had better health-related quality of life than those who had their eye enucleated and were more likely to have higher (better) scores on the VF questionnaire items. On the other hand, the binocular vision and time after the treatment correlated with the quality of life in long-term follow-up.


[In vitro study on the cytotoxicity of strontium substituted hydroxyapatite].
To evaluate the cytotoxicity of strontium substituted hydroxyapatite. Cell Relative Growth Rate(RGR) method, MTT assay and Flow Cytometry(FCM) method were used, and the strontium substituted hydroxyapatite contained different strontium concentration(0%,1%,5%,10%,100%). It was found that there's no apparent cytotoxicity of all the strontium substituted hydroxyapatite,but the cytotoxicity increased as the strontium concentration raised. As the FCM method appeared, there was no apparent difference between the pure hydroxyapatite and 1%,5% strontium substituted hydroxyapatite. Strontium substituted hydroxyapatite has good biocompatibility, and 10%,100% strontium substituted hydroxyapatite has weak cytotoxicity.


Crossing the termination shock into the heliosheath: magnetic fields.
Magnetic fields measured by Voyager 1 show that the spacecraft crossed or was crossed by the termination shock on about 16 December 2004 at 94.0 astronomical units. An estimate of the compression ratio of the magnetic field strength B (+/- standard error of the mean) across the shock is B2/B1 = 3.05 +/- 0.04, but ratios in the range from 2 to 4 are admissible. The average B in the heliosheath from day 1 through day 110 of 2005 was 0.136 +/- 0.035 nanoteslas, approximately 4.2 times that predicted by Parker's model for B. The magnetic field in the heliosheath from day 361 of 2004 through day 110 of 2005 was pointing away from the Sun along the Parker spiral. The probability distribution of hourly averages of B in the heliosheath is a Gaussian distribution. The cosmic ray intensity increased when B was relatively large in the heliosheath.


Band keratopathy with bilateral deafness as a presenting sign of hyperparathyroidism.
An unusual case of hyperparathyroidism is reported in which calcification of the cornea was the presenting clinical and diagnostic sign. Early recognition of this condition may be of lifesaving importance.


Stabilities of hydroxyl radical spin adducts of PBN-type spin traps.
The stability of the hydroxyl spin adduct of nine different PBN-type spin traps has been examined in phosphate buffer solutions of various pH. The hydroxyl adduct is produced by short illumination of hydrogen peroxide with UV light in the presence of spin trap and the decay of its EPR signal followed. The stability measured by the half life of the first-order decay is strongly dependent on the pH of the solution and the structure of the aromatic ring used in the trap. All hydroxyl adducts are more stable in acidic media. tert-Butyl hydroaminoxyl is detected as a degradation product of the hydroxyl adduct from all spin traps.


Association between ambient air particulate matter and human health impacts in northern Thailand.
Air pollution in Thailand is regarded as a serious health threat, especially in the northern region. High levels of particulate matter (PM2.5 and PM10) are strongly linked to severe health consequences and mortality. This study analyzed the relationship between exposure to ambient concentrations of PM2.5 and PM10 by using data from the Pollution Control Department of Thailand and the burden of disease due to an increase in the ambient particulate matter concentrations in northern Thailand. This study was conducted using the Life Cycle Assessment methodology considering the human health damage impact category in the ReCiPe 2016 method. The results revealed that the annual average years of life lived with disability from ambient PM2.5 in northern Thailand is about 41,372 years, while from PM10 it is about 59,064 years per 100,000 population. The number of deaths from lung cancer and cardiopulmonary diseases caused by PM2.5 were approximately 0.04% and 0.06% of the population of northern Thailand, respectively. Deaths due to lung cancer and cardiopulmonary diseases caused by PM10, on the other hand, were approximately 0.06% and 0.08%, respectively. The findings expressed the actual severity of the impact of air pollution on human health. It can provide valuable insights for organizations in setting strategies to address air pollution. Organizations can build well-informed strategies and turn them into legal plans by exploiting the study's findings. This ensures that their efforts to tackle air pollution are successful, in accordance with regulations, and contribute to a healthier, more sustainable future guidelines on appropriate practices of air pollution act/policy linkage with climate change mitigation.


Predictive value of human papillomavirus in oropharyngeal carcinoma treated with radiotherapy: An updated systematic review and meta-analysis of 30 trials.
Human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OSCC) is emerging as a different subtype of head and neck cancer. The authors conducted a systematic review and meta-analysis to examine the predictive role of HPV in patients with OSCC treated with radiotherapy-based modality therapy. The authors performed a PubMed search to identify published trials that evaluated the outcome of HPV+ OSCC treated with radiotherapy. Hazard ratios (HRs) were extracted and pooled by using random or fixed effects models. The primary endpoints were overall survival (OS), disease-specific survival, (DSS), and disease-free survival (DFS). Thirty trials were available for HPV analysis. HPV+ status is associated with better OS (HR = 0.33; p < .00001), DSS (HR = 0.24; p < .00001), and DFS (HR = 0.31; p < .00001). HPV+ OSCC has a better survival compared to HPV-negative disease when treated with radiotherapy-based modality therapy.


Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.
Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects. The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.


Testing genetic modifiers of behavior and response to atomoxetine in autism spectrum disorder with ADHD.
Frequent non-pathogenic genetic variants may act as moderators of phenotypic severity for complex disorders such as autism spectrum disorder (ASD). We previously identified polymorphisms affecting mRNA expression of candidate genes, including tryptophan hydroxylase 2 (TPH2), dopamine beta hydroxylase (DBH), and dopamine transporter (DAT, SLC6A3). We compare genotypes and (1) clinical response to atomoxetine, (2) scores from the Autism Diagnostic Interview-Revised (ADI-R), and (3) severity of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in a cohort of patients with ASD from multiple study sites. There was no association between CYP2D6 metabolizer status and atomoxetine response. TPH2 rs7305115 genotype was associated with ADI-R Restrictive/Repetitive Behavior score (p=0.03). DBH rs1611115 genotype was associated with ADI-R Social score (p=0.002) and Restrictive/Repetitive Behavior score (p=0.04). The DAT intron 8 5/6 repeat was associated with ADHD symptoms (ABC Hyperactivity p=0.01 and SNAP ADHD p=0.03), replicating a previous finding. We find associations between ASD phenotypes and regulatory variants in catecholamine biosynthesis genes. This work may help guide future genetics studies related to ASD.


Natural human apoA-I mutations L141RPisa and L159RFIN alter HDL structure and functionality and promote atherosclerosis development in mice.
Mutations in human apolipoprotein A-I (apoA-I) are associated with low high-density lipoprotein (HDL) cholesterol levels and pathological conditions such as premature atherosclerosis and amyloidosis. In this study we functionally characterized two natural human apoA-I mutations, L141RPisa and L159RFIN, in vivo. We generated transgenic mice expressing either wild-type (WT) or the two mutant forms of human apoA-I on a mouse apoA-I(-/-) background and analyzed for abnormalities in their lipid and lipoprotein profiles. HDL structure and functionality, as well as atherosclerosis development following a 14-week high-fat diet were assessed in these mice. The expression of either apoA-I mutant was associated with markedly reduced serum apoA-I (<10% of WT apoA-I), total and HDL-cholesterol levels (∼20% and ∼7% of WT apoA-I, respectively) and the formation of few small size HDL particles with preβ2 and α3, α4 electrophoretic mobility. HDL particles containing either of the two apoA-I mutants exhibited attenuated anti-oxidative properties as indicated by their inability to prevent low-density lipoprotein oxidation, and by decreased activities of paraoxonase-1 and platelet-activating factor acetylhydrolase. However, the apoA-I(L141R)Pisa or apoA-I(L159R)FIN-containing HDL particles demonstrated increased capacity to promote ATP-Binding Cassette Transporter A1-mediated cholesterol efflux from macrophages. Expression of apoA-I(L141R)Pisa or apoA-I(L159R)FIN mutations in mice was associated with increased diet-induced atherosclerosis compared to either WT apoA-I transgenic or apoA-I(-/-) mice. These findings suggest that natural apoA-I mutations L141RPisa and L159RFIN affect the biogenesis and the functionality of HDL in vivo and predispose to diet-induced atherosclerosis in the absence of any other genetic defect.


[Facial nerve reanimation by partial section of the hypoglossal nerve and mini mastoidectomy].
Hypoglossal-facial anastomosis is the gold standard treatment for facial reanimation in those cases where the facial nerve has been damaged near the brainstem. The technique that requires temporal bone drilling and partial section of the hypoglossal nerve is usually preferred. This technique diminishes tongue morbidity while preserves good facial reanimation. The goal of the present work is to describe a simple technique to expose the mastoid portion of the facial nerve. The mastoid portion of the facial nerve runs on the anterior wall of the mastoid process; mean 18+/-3 mm deeply to the lateral wall. The supramastoid crest has to be identified; a parallel line is marked from the crest to the mastoid tip, and bone drilling is performed anterior to the line. Once the facial nerve is identified, proximal and distal dissection is performed. This limited approach allows to a safe exposure of the mastoid segment of the facial nerve. This procedure is technically less demanding but should be restricted to hypoglossal-facial anastomosis. Surgeons not fully experienced in temporal bone drilling can do this simple approach after performing some laboratory practice.


Effect of Care Capacity on Stroke Patients' Recovery in Activities of Daily Living: A Multi-Hospital Study.
This study aimed to investigate whether care capacity for patients following stroke contributes to improved activities of daily living (ADL) at discharge from hospital based on the degree of stroke severity. Retrospective, observational, longitudinal study. Acute phase hospitals. From 2005 to 2011, 5006 patients with stroke at acute phase hospitals were registered in a database. There were 2501 individuals from 11 hospitals who met the following four criteria: (1) a pre-stroke modified Rankin Scale (mRS) score of 0-3; (2) admission to hospital within 7 days of suffering a stroke; (3) ischemic or hemorrhagic stroke; and (4) staying in hospital for 8-60 days. The main outcome measure was the Functional Independence Measure (FIM, version 3.0) score at discharge. The FIM is an internationally used scale, which is used as an ADL outcome assessment scale for after rehabilitation. Among patients with stroke, those with care capacity had higher FIM scores at hospital discharge than did those without care capacity (unstandardized coefficient = 2.3, P = 0.015). Examination of this relationship by stroke severity showed that the FIM score at discharge was only significantly higher in patients who suffered from a moderate to severe stroke (unstandardized coefficient = 7.0, P = 0.040). No associations were observed in patients who suffered from minor, moderate, or severe stroke. These results suggest that care capacity facilitates total recovery of the FIM, especially among patients who suffer from a moderate to severe stroke.


Developmental quotient to estimate intelligence in autism spectrum disorder.
Autism spectrum disorders (ASD) are characterized by persistent deficits in social communication and social interaction across contexts, and are associated with restricted patterns of behavior. The developmental quotient (DQ) is based on the developmental age and chronological age of children. This study investigated the utility of the DQ to estimate cognitive ability in young children with ASD. The DQ and intelligence quotient (IQ) were assessed using the Kyoto Scale of Psychological Development 2001 (KSPD) and Wechsler Intelligence Scale for Children-III (WISC-III), respectively. The correlation between the DQ and IQ was then analyzed among children with ASD. We enrolled 18 children with ASD (16 boys, two girls; age, 63.6 ± 9.4 months; age range, 45-83 months). Overall, Cognitive-Adaptive and Language-Social DQ scores were significantly correlated with IQ score in the full scale, verbal, and performance domains. Full-scale IQ and overall DQ had a linear correlation (y = -22.747 + 1.177x, R2 = 0.677, R = 0.823). The DQ scores obtained using the KSPD were a reasonable estimate of cognitive ability in children with ASD. The KSPD may be a useful alternative to the WISC-III for young children with ASD and could facilitate earlier assessment.


[Identification of mycobacteria under routine clinical conditions].
A simplified system for identification of mycobacteria in routine is presented and discussed. By this way costs for staff and material can be reduced.


[Atopic dermatitis of the adult].
Atopic dermatitis (AD) of the adult is a common skin disease. Its prevalence has greatly increased during the past decades. AD is commonly associated with other atopic disorders. Its impact on quality of life is often underestimated. Various immunopathologic mechanisms are involved in AD: innate epidermal barrier dysfunction due to filaggrin gene mutations, innate and adaptative abnormalities of the immune system (an initial Th2 phase precedes a chronic Th1 phase), intestinal and cutaneous microbiomes dysbiosis, and environmental factors. Diagnosis of AD is clinical and there is no predictive biomarker of future severity. The main differential diagnoses are: scabies, psoriasis, cutaneous adverse reaction, cutaneous T cell lymphoma, primary immunodeficiency, and Netherton's syndrome. Therapeutic management is challenging and should integrate a therapeutic education program. Topical corticosteroids are the first line treatment, including a preliminary assessment of possible topical corticosteroids phobia. Systemic treatments are recommended in severe, chronic and resistant AD, after careful evaluation in a reference centre. Dupilumab, an IL4/IL13 inhibitor, might be the first effective targeted therapy in AD, whereas therapies that specifically target the mechanisms of pruritus represent an exciting perspective.


Plasma eicosanoids, platelet function and cold sensitivity.
As abnormal eicosanoid (prostaglandin) metabolism has been suggested as a factor in the aetiology of vasospastic diseases we have measured levels of stable eicosanoid metabolites using a radioimmunoassay in 30 normal subjects and 31 patients with Raynaud's phenomenon. There were 13 patients with primary Raynaud's, ten with Raynaud's secondary to scleroderma and eight men with vibration white finger (VWF) disease. We have also measured platelet aggregation to adenosine diphosphate (ADP), collagen and adrenaline in 19 normal subjects, 22 patients with primary Raynaud's, 12 with Raynaud's secondary to scleroderma and 14 men with VWF. When compared with our normal subjects, patients with VWF have an elevated thromboxane B2 level, with a normal 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) level. Their platelets are less sensitive to ADP and collagen. Patients with primary and secondary Raynaud's have elevated thromboxane B2 levels but this is much more marked in the secondary group. Patients with primary Raynaud's have a normal 6-keto-PGF1 alpha level but in patients with secondary Raynaud's the 6-keto-PGF1 alpha level is markedly raised. The platelets from both groups are more sensitive to ADP and collagen and this is more marked in the secondary group. Whether these phenomena are a cause or an effect of vasospasm remains unknown.


Striated muscle function, regeneration, and repair.
As the only striated muscle tissues in the body, skeletal and cardiac muscle share numerous structural and functional characteristics, while exhibiting vastly different size and regenerative potential. Healthy skeletal muscle harbors a robust regenerative response that becomes inadequate after large muscle loss or in degenerative pathologies and aging. In contrast, the mammalian heart loses its regenerative capacity shortly after birth, leaving it susceptible to permanent damage by acute injury or chronic disease. In this review, we compare and contrast the physiology and regenerative potential of native skeletal and cardiac muscles, mechanisms underlying striated muscle dysfunction, and bioengineering strategies to treat muscle disorders. We focus on different sources for cellular therapy, biomaterials to augment the endogenous regenerative response, and progress in engineering and application of mature striated muscle tissues in vitro and in vivo. Finally, we discuss the challenges and perspectives in translating muscle bioengineering strategies to clinical practice.


Cortico-cortical inhibition of the motor cortical area projecting to sternocleidomastoid muscle in normals and patients with spasmodic torticollis or essential tremor.
To investigate whether the cortico-cortical inhibition originally reported for the human hand motor area is present in the motor cortex for sternocleidomastoid muscle (SCM) and to evaluate the amount of inhibition in spasmodic torticollis and essential tremor. Subjects were 14 normal healthy volunteers, 10 patients with spasmodic torticollis and 5 with essential tremor involving neck muscles. A paired-pulse magnetic stimulation was performed for the SCMs and first dorsal interosseous muscles (FDIs). In normal subjects, a subthreshold magnetic conditioning stimulus suppressed responses to a suprathreshold magnetic test stimulus when their interval was 1-5 ms in SCM. This indicates that the similar cortico-cortical inhibitory mechanism is present in the motor cortex for SCM as in the hand motor area. In the patients with spasmodic torticollis, the cortico-cortical inhibitory effect was reduced or absent in SCM, but normal in the FDI. In contrast, in patients with essential tremor, normal cortico-cortical inhibition was seen in both the SCM and FDI. The cortico-cortical inhibitory mechanisms of the motor cortex for SCM can be studied by a paired-pulse magnetic stimulation method. Our result of reduced cortico-cortical inhibition in torticollis patients suggests abnormal excitability (hyperexcitable or disinhibited) of the motor cortex for SCM in spasmodic torticollis.


Determination of left-sided pressure gradients by utilizing Doppler aortic and mitral regurgitant signals: validation by simultaneous dual catheter and Doppler studies.
Continuous wave Doppler echocardiography is an accurate and reproducible method for determination of intracardiac pressure gradients in stenotic valve lesions and right-sided regurgitant lesions. Twenty-three patients with either mitral or aortic regurgitation underwent simultaneous continuous wave Doppler and dual catheter pressure recordings to determine if instantaneous pressure gradients can be accurately determined by Doppler ultrasound in left-sided regurgitant valve lesions. Using the modified Bernoulli equation, the maximal and mean pressure gradients between the left ventricle and left atrium were determined by continuous wave Doppler ultrasound in patients with mitral regurgitation and compared with simultaneous catheter-derived pressures. The mean and end-diastolic pressure gradients between the aorta and left ventricle were determined by continuous wave Doppler ultrasound in patients with aortic regurgitation and compared with simultaneous catheter-derived pressures. Diastolic half-times by both continuous wave Doppler ultrasound and catheter pressures were compared in patients with aortic regurgitation. There was a linear correlation between the mean gradients in all patients (r = 0.94; SEE = 6 mm Hg) with a similar correlation between the instantaneous gradients (r = 0.98; SEE = 8 mm Hg). There was a linear correlation between diastolic half-times by catheter and Doppler ultrasound (r = 0.95; SEE = 39 ms). As with other valvular lesions, continuous wave Doppler echocardiography can be used in patients with mitral or aortic regurgitation to accurately determine intracardiac pressure gradients.


Gamete Binning to Achieve Haplotype-Resolved Genome Assembly.
Haplotype-resolved genome assemblies remain a challenge in practice. Here, we provide a step-by-step guide on gamete binning, a method to generate haplotype-resolved genome assemblies for diploid species. The protocol starts by phasing heterozygous variants to individual haplotypes of specific chromosomes using the genome information of individual haploid gametes of the focal individual. Using phased variants, the whole-genome sequencing reads from the diploid genome can be genotyped and assigned into groups, which represent the individual haplotypes of each of the chromosomes. Finally, haplotype-specific chromosomes can be assembled independently using standard assembly tools. First applications of gamete binning revealed a haplotyping accuracy over 99%, which outperformed sequence-only or Hi-C-based haplotype-resolved genome assemblies.Availability: github.com/schneebergerlab/GameteBinning_prac .


Food palatability and hunger modulated effects of CGS 9896 and CGS 8216 on food intake.
The effect of food palatability and duration of food deprivation on the modulation of food intake by two benzodiazepine receptor (BDZR) ligands, CGS 9896 and CGS 8216, were investigated. Three diets differing in palatability (high, medium, or standard) and three different periods of food deprivation (0, 16, or 24 h) were used in all combinations to compare the effect of these variations on the observed modulation of food consumption by both BDZR ligands. Increasing diet palatability and/or food deprivation increased the baseline food consumption and reduced the sensitivity of the test to the detection of the hyperphagic effect of CGS 9896 but increased the sensitivity to detect the anorexic effect of CGS 8216. Only for the intermediate conditions of food deprivation (16 h) and for a standard or medium palatable diet were both significant hyperphagic effect of CGS 9896 and anorexic effect of CGS 8216 detected. Neither increased palatability nor hunger enhanced the modulation of feeding, indicating that neither "taste preference" nor "hunger" is the key factor in the mechanism of BDZR ligand-induced feeding response.


Stabilization of placental aromatase by dithiothreitol in the presence of oxidizing agents.
Cumene hydroperoxide, sodium periodate and iodosobenzene were not able to support aromatization by placental microsomes in the absence of NADPH or molecular oxygen. In the presence of these oxidizing agents and NADPH, aromatase was slowly inactivated. Dithiothreitol (10mM) prevented the loss of aromatizing activity in the presence of these compounds. One function of dithiothreitol may be to protect aromatase by scavenging harmful oxidizing agents.


The VNTR polymorphism of the CLEC4M gene and susceptibility to HIV-1 infection in Han Chinese population.
C-type lectin domain family 4, member M (CLEC4M, also known as DC-SIGNR) is a C-type lectin that functions as a transreceptor for human immunodeficiency virus-1 (HIV-1). The relationship between variable number tandem repeat (VNTR) polymorphism of the DC-SIGNR gene and susceptibility to HIV-1 infection has been under debate. In the present study, a cohort of 287 HIV-1 seropositive patients and 388 ethnically age-matched healthy controls from Han Chinese population were enrolled in order to determine the influence of host genetic factors on HIV-1 infection. A total of 11 genotypes and 5 alleles were found in our population. A cross-sectional comparison between HIV-1 seropositive patients and healthy controls did not reveal significant differences with regards to DC-SIGNR genotype distribution, allele frequencies and homozygotes proportion. In addition, previous studies showed that DC-SIGNR might play different roles in different HIV infection routes. We stratified the patients into two subgroups: sexual contact patients and intravenous drug abuser/blood transfusion patients. Our results showed the frequencies of DC-SIGNR genotypes/alleles in these two subgroups were similar. To our knowledge, this is the first study performed in Northern Chinese. Our findings suggested that DC-SIGNR neck region VNTR polymorphism was not directly associated with hosts' predisposition for HIV-1 infection and not associated with the HIV-1 routes of infection. By lack of HIV-1 exposed seronegative (HESN) individuals and relative small sample size in present study made our conclusions not strong enough. In addition, the role of the DC-DIGNR neck region in different HIV-1 infection routes remains open for future study.


Oculomotor factors in the aetiology of occupational cervicobrachial diseases (OCD).
The traditional posture-ergonomic perspective on the aetiology of Occupational Cervicobrachial Disease (OCD) is discussed and criticized in the light of present knowledge of oculomotor strain during sustained visual work at short distances. Two experiments on ocularly induced neck muscular tension are reported. In both experiments EMG's were taken from six different muscles in the head, neck and shoulder region during a visual discrimination task. In Experiment 1, accommodation and fusion requirements were systematically varied by changing viewing distance in combination with the application of minus-lenses and base-out prisms. EMG was shown to increase as a function of accommodation and fusion load. In Experiment 2, a clinical population with severe and long lasting neck and shoulder problems and inappropriate optical corrections was studied with the same experimental design. EMG was shown to decrease when habitual corrections were replaced by more appropriate ones.


Sudden cardiac death from acute fluoride intoxication: the role of potassium.
The mechanism of sudden cardiac death following acute fluoride intoxication has been thought to result from profound hypocalcemia produced by the precipitation of calcium fluoride salts. In studies of a canine model, the onset of lethal ventricular arrhythmias was temporally more associated with an elevation of serum potassium than with a drop in serum calcium. Fluoride-induced hyperkalemia could not be prevented with glucose, insulin, or bicarbonate. In the erythrocytes, a five-minute exposure to 10 mM NaF caused a 50% increase in extracellular potassium concentrations after 12 hours compared to control erythrocyte suspensions (P less than .001). The total potassium efflux after 12 hours of incubation was linearly related to the log of fluoride contact time (r, 0.886; P less than .001). The treatment of fluoride-induced hyperkalemia may depend on removal of fluoride and potassium.


Does testosterone predict women's preference for facial masculinity?
The influence of sex hormones on women's mate preferences has been an intensively discussed topic for more than a decade. Yet the extent to which levels of sex hormones, and testosterone in particular, influence women's mate preferences is unclear. Thus, the current study used multilevel modelling to investigate putative relationships between salivary testosterone and facial masculinity preferences in a sample of 68 women, while controlling for their age, partnership status, and sociosexuality. We found no significant associations between masculinity preferences and either individual differences or within-woman changes in testosterone. We did find however, that sociosexuality was positively correlated with masculinity preferences. Although it has previously been suggested that testosterone is related to women's facial masculinity preference, our data do not support this proposal.


The effect of outdoor air and indoor human activity on mass concentrations of PM(10), PM(2.5), and PM(1) in a classroom.
The 12-h mass concentration of PM(10), PM(2.5), and PM(1) was measured in a lecturing room by means of three co-located Harvard impactors. The filters were changed at 8 AM and at 8 PM to cover the periods of presence and absence of students. Concentrations were assessed by gravimetry. Ambient PM(10) data were available for corresponding 12-h intervals from the nearest state air-quality-monitoring network station. The data were pooled into four periods according to the presence and absence of students-Monday-Thursday day (workday daytime), Monday-Thursday night (workday night), Friday-Sunday day (weekend daytime), and Friday-Sunday night (weekend night). Average indoor workday daytime concentrations were 42.3, 21.9 and 13.7 microgm(-3), workday night were 20.9, 19.1 and 15.2 microgm(-3), weekend daytime were 21.9, 18.1 and 11.4 microgm(-3), and weekend night were 24.5, 21.3, and 15.6 microgm(-3) for PM(10), PM(2.5), and PM(1), respectively. The highest 12-h mean, median, and maximum (42.3, 43.0, and 76.2 microgm(-3), respectively) indoor concentrations were recorded on workdays during the daytime for PM(10). The statistically significant (r=0.68,P<0.0009) correlation between the number of students per hour per day and the indoor coarse fraction calculated as PM(10--2.5) during daytime on workdays indicates that the presence of people is an important source of coarse particles indoor. On workdays, the daytime PM(10) indoor/outdoor ratio was positively associated (r=0.93) with an increasing indoor coarse fraction (PM(10--2.5)), also indicating that an important portion of indoor PM(10) had its source inside the classroom. With the exception of the calculated coarse fraction (PM(10--2.5)), all of the measured indoor particulate matter fractions were significantly highly correlated with outdoor PM(10) and negatively correlated with wind velocity, showing that outdoor levels of particles influence their indoor concentrations.


Amputation of left foot macrodactyly improve quality of life for a toddler: a case report from Tigray, Northern Ethiopia.
Macrodactyly is an uncommon, not inherited congenital malformation of the digit with unknown prevalence and path of pathogenesis. The condition was described in 1940 and since then 107 cases were reported. Manifestations may mislead the diagnosis of hemangiomas and lymphangiomatosis. There are different options for treatment without a clear consensus. The authors are presenting a macrodactyly case that improved the quality of his life after he underwent surgical amputation of the toes. The authors had a case of a 2-year and 4-month-old male child presented with progressive growth of the left foot toes; which started since birth in the 4th toe and then involved 3rd and 5th toe later; resulting in deformity and difficulty in wearing shoes. Physical examination; showed left foot enlargements of the 3rd-5th toes. X-ray of the left foot was done he was diagnosed to have macrodactyly. Under general anesthesia metatarsophalangeal joint of the 4th-5th toe and distal interphalangeal joint of the 3rd toe, disarticulation was done. The patient is doing okay on follow-up for the last year. Consistently with other case reports from Korea, Tanzania, and Congo our patient presented with a primary type of left foot macrodactyly in his early life, and he was successfully managed with amputation of the affected digits. This is one of the rare cases which needs a high index of suspicion to diagnose and treat early to improve quality of life. Amputation is the most important management in resources limited areas.


Functional Effects of a Tissue-Engineered Cardiac Patch From Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Rat Infarct Model.
A tissue-engineered cardiac patch provides a method to deliver cardiomyoctes to the injured myocardium with high cell retention and large, controlled infarct coverage, enhancing the ability of cells to limit remodeling after infarction. The patch environment can also yield increased survival. In the present study, we sought to assess the efficacy of a cardiac patch made from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to engraft and limit left ventricular (LV) remodeling acutely after infarction. Cardiac patches were created from hiPSC-CMs and human pericytes (PCs) entrapped in a fibrin gel and implanted acutely onto athymic rat hearts. hiPSC-CMs not only remained viable after in vivo culture, but also increased in number by as much as twofold, consistent with colocalization of human nuclear antigen, cardiac troponin T, and Ki-67 staining. CM+PC patches led to reduced infarct sizes compared with myocardial infarction-only controls at week 4, and CM+PC patch recipient hearts exhibited greater fractional shortening over all groups at both 1 and 4 weeks after transplantation. However, a decline occurred in fractional shortening for all groups over 4 weeks, and LV thinning was not mitigated. CM+PC patches became vascularized in vivo, and microvessels were more abundant in the host myocardium border zone, suggesting a paracrine mechanism for the improved cardiac function. PCs in a PC-only control patch did not survive 4 weeks in vivo. Our results indicate that cardiac patches containing hiPSC-CMs engraft onto acute infarcts, and the hiPSC-CMs survive, proliferate, and contribute to a reduction in infarct size and improvements in cardiac function. In the present study, a cardiac patch was created from human induced pluripotent stem cell-derived cardiomyocytes and human pericytes entrapped in a fibrin gel, and it was transplanted onto infarcted rat myocardium. It was found that a patch that contained both cardiomyocytes and pericytes survived transplantation and resulted in improved cardiac function and a reduced infarct size compared with controls.


Endoscopic endonasal transmaxillary approach and endoscopic sublabial transmaxillary approach: surgical decision-making and implications of the nasolacrimal duct.
The nasolacrimal duct resides in the wall of the medial nasal cavity and influences minimal access endoscopic transmaxillary approaches to the lateral skull base. We describe an algorithm for surgical approach selection on the basis of the relationship of the target lesion to a line drawn from the anterior nasal SEptum through the Nasolacrimal Duct to the lesion (i.e., SEND line). We use the SEND line to estimate the lateral extent in the endonasal middle meatal transmaxillary approach, where the surgeon has good surgical freedom without the use of angled instruments and endoscopes. Lesions with an epicenter lateral to the SEND line were addressed through a sublabial anterior antrostomy transmaxillary corridor. Tumors with a more medially located epicenter, such as those involving the lateral sphenoid sinus and pterygoid plates, were addressed through the endonasal middle meatal corridor. Extensive tumors involving both domains were addressed through a combination approach. We describe three instructive cases in which the approach selection was determined in part by preoperative assessment of the location of the tumor relative to the SEND line. The endoscopic sublabial transmaxillary and endoscopic endonasal middle meatal transmaxillary approaches are complementary corridors to the anterior skull base that can be used independently or in combination. The location of the target lesion relative to the SEND line as determined on preoperative imaging can serve as a guide for surgical decision making.


Diadenosine-5-phosphate exerts A1-receptor-mediated proarrhythmic effects in rabbit atrial myocardium.
(1) Diadenosine polyphosphates have been described to be present in the myocardium and exert purinergic- and nonreceptor-mediated effects. Since the electrophysiological properties of atrial myocardium are effectively regulated by A(1) receptors, we investigated the effect of diadenosine pentaphosphate (Ap(5)A) in rabbit myocardium. (2) Parameters of supraventricular electrophysiology and atrial vulnerability were measured in Langendorff-perfused rabbit hearts. Muscarinic potassium current (I(K(ACh/Ado))) and ATP-sensitive potassium current (I(K(ATP))) were measured by using the whole-cell voltage clamp method. (3) Ap(5)A prolonged the cycle length of spontaneously beating Langendorff perfused hearts from 225+/-14 (control) to 1823+/-400 ms (Ap(5)A 50 micro M; n=6; P<0.05). This effect was paralleled by higher degree of atrio-ventricular block. Atrial effective refractory period (AERP) in control hearts was 84+/-14 ms (n=6). Ap(5)A>/=1 micro M reduced AERP (100 micro M, 58+/-11 ms; n=6). (4) Extrastimuli delivered to hearts perfused with Ap(5)A- or adenosine (>/= micro M)-induced atrial fibrillation, the incidence of which correlated to the concentration added to the perfusate. The selective A(1)-receptor antagonist CPX (20 micro M) inhibited the Ap(5)A- and adenosine-induced decrease of AERP. Atrial fibrillation was no longer observed in the presence of CPX. (5) The described Ap(5)A-induced effects in the multicellular preparation were enhanced by dipyridamole (10 micro M), which is a cellular adenosine uptake inhibitor. Dipyridamole-induced enhancement was inhibited by CPX. (6) Ap(5)A (</=1 mM) did neither induce I(K(Ado)) nor I(K(ATP)). No effect on activated I(K(Ado/ATP)) was observed in myocytes superfused with Ap(5)A. However, effluents from Langendorff hearts perfused with Ap(5)A 100 micro M activated I(K(Ado)) by using A(1) receptors. (7) Ap(5)A did not activate A(1) receptors in rabbit atrial myocytes. The Ap(5)A induced A(1)-receptor-mediated effects on supraventricular electrophysiology and vulnerability suggest that in the multicellular preparation Ap(5)A is hydrolyzed to yield adenosine, which acts via A(1) receptors. An influence on atrial electrophysiology or a facilitation of atrial fibrillation under conditions resulting in increased interstitial Ap(5)A concentrations might be of physiological/pathophysiological relevance.


Direct assignment of citrate synthase (CS) gene to human chromosome 12 in man-mouse somatic cell hybrids.
A panel of twenty independently derived clones of man-mouse somatic cell hybrids isolated from fusions involving eight different parent cell combinations simultaneously analyzed for human chromosomes, citrate synthase, and a large number of other enzyme markers firmly or tentatively assigned to individual human chromosomes have provided direct evidence for a firm assignment of the structural gene coding for citrate synthase (CS) to human chromosome 12.


Ivermectin synergizes sorafenib in hepatocellular carcinoma via targeting multiple oncogenic pathways.
Advanced hepatocellular carcinoma (HCC) results in generally poor clinical outcomes and necessitates better therapeutic strategies. Ivermectin, which is an existing anti-parasitic drug, has been recently identified as a novel anti-cancer drug. In line with previous efforts, this work demonstrates the translational potential of ivermectin to treat advanced HCC. We demonstrated that ivermectin at clinically relevant concentrations was active against growth and survival in multiple HCC cell lines. We showed that ivermectin had the potential to inhibit metastasis and target HCC stem cell functions. Mechanism studies correlated well with cellular phenotypes observed in ivermectin-treated cells, and demonstrated inhibition of mTOR/STAT3 pathway, suppression of epithelial mesenchymal transition (EMT) and reduced expression of stem cell markers. We further demonstrated that ivermectin inhibited tumor formation and growth in HCC xenograft mouse model, without causing significant toxicity in the mice. Using combination index (CI), we showed that ivermectin and sorafenib were synergistic in HCC in vitro, and this was further confirmed in vivo. Our work demonstrates the potent anti-HCC activities of ivermectin and its multiple targets on essential oncogenic pathways. Our findings provide preclinical evidence to initialize clinical trial using ivermectin and sorafenib for treating advanced HCC.


Prediction of response to cardiac resynchronization therapy using a multi-feature learning method.
We hypothesized that a multiparametric evaluation, based on the combination of electrocardiographic and echocardiographic parameters, could enhance the appraisal of the likelihood of reverse remodeling and prognosis of favorable clinical evolution to improve the response of cardiac resynchronization therapy (CRT). Three hundred and twenty-three heart failure patients were retrospectively included in this multicenter study. 221 patients (68%) were responders, defined by a decrease in left ventricle end-systolic volume ≥15% at the 6-month follow-up. In addition, strain data coming from echocardiography were analyzed with custom-made signal processing methods. Integrals of regional longitudinal strain signals from the beginning of the cardiac cycle to strain peak and to the instant of aortic valve closure were analyzed. QRS duration, septal flash and different other features manually extracted were also included in the analysis. The random forest (RF) method was applied to analyze the relative feature importance, to select the most significant features and to build an ensemble classifier with the objective of predicting response to CRT. The set of most significant features was composed of Septal Flash, E, E/A, E/EA, QRS, left ventricular end-diastolic volume and eight features extracted from strain curves. A Monte Carlo cross-validation method with 100 runs was applied, using, in each run, different random sets of 80% of patients for training and 20% for testing. Results show a mean area under the curve (AUC) of 0.809 with a standard deviation of 0.05. A multiparametric approach using a combination of echo-based parameters of left ventricular dyssynchrony and QRS duration helped to improve the prediction of the response to cardiac resynchronization therapy.


Significance of radiofrequency ablation in large solid benign thyroid nodules.
The aim of this study is to explore efficacy and safety for radiofrequency ablation (RFA) among cases attacked by large benign solid thyroid nodules, mainly focusing on volume reduction, complication rate, and thyroid function. From June 2015 to November 2019, 24 patients with 25 large benign solid thyroid nodules (more than 25 ml) underwent single or sequential RFA in our institution. Eleven nodules achieved complete ablation after single RFA, whereas the other 14 nodules received sequential RFA. Volume reduction in large nodules was evaluated. Following single or sequential RFA, all patients received clinical and ultrasound evaluations, and the median follow-up duration among them was 23.5 months. Technical success, complication rate, and recurrence rate were assessed as well. In single RFA group, volume reduction ranged from 62.6% to 99.4% (mean ± SD, 93.6 ± 9.9%) 6 months after RFA. In sequential RFA group, volume reduction ranged from 30.6% to 92.9% (mean ± SD, 67.4 ± 17.8%) after the first RFA and was between 83.4% and 98.4% (mean ± SD, 94.8± 3.8%) 6 months after the second RFA. The concentrations of FT3 and FT4 increased slightly 1 day after RFA and returned to normal level 1 month after. Single or sequential RFA is safe and effective in treating large benign solid thyroid nodules (more than 25 ml) that cause obvious compressive symptoms. Hence, compression symptoms and cosmetic conditions could be effectively improved through single or sequential RFA without marginal recurrence.


Kin recognition signals in adult faces.
Maloney and Dal Martello [Maloney, L.T., Dal Martello, M.F. (2006). Kin recognition and the perceived facial similarity of children. Journal of Vision, 6(10), 1047-1056. http://www.journalofvision.org/6/10/4/] reported that similarity ratings of pairs of related and unrelated children were almost perfect predictors of the probability that those children were judged as being siblings by a second group of observers. Surprisingly, similarity ratings were poor predictors of whether a pair was same-sex or opposite-sex, suggesting that people ignore cues that are uninformative about kinship when making similarity judgments of faces. Using adult sibling faces, we find that similarity ratings for same-sex pairs were significantly higher than for opposite-sex pairs, suggesting that similarity judgments of adult faces are not entirely synonymous with kinship judgments.


Uric Acid Expression in Carotid Atherosclerotic Plaque and Serum Uric Acid Are Associated With Cerebrovascular Events.
Uric acid (UA) concentration within carotid plaque and its association with cerebrovascular events have not been detected or quantified. Systemically, serum UA is a marker of inflammation and risk factor for atherosclerosis. However, its association with carotid plaque instability and stroke pathogenesis remains unclear. In patients undergoing carotid endarterectomy, we aimed to determine whether UA is present differentially in symptomatic versus asymptomatic carotid plaques and whether serum UA is associated with cerebrovascular symptoms (stroke, transient ischemic attack, or amaurosis fugax). Carotid atherosclerotic plaques were collected during carotid endarterectomy. The presence of UA was assessed using Gomori methenamine silver staining as well as anti-UA immunohistochemical staining and its quantity measured using an enzymatic colorimetric assay. Clinical information was obtained through a retrospective review of data. UA was more commonly detected in symptomatic (n=23) compared with asymptomatic (n=9) carotid plaques by Gomori methenamine silver (20 [86.9%] versus 2 [22.2%]; P=0.001) and anti-UA immunohistochemistry (16 [69.5%] versus 1 [11.1%]; P=0.004). UA concentration was higher in symptomatic rather than asymptomatic plaques (25.1 [9.5] versus 17.9 [3.8] µg/g; P=0.021). Before carotid endarterectomy, serum UA levels were higher in symptomatic (n=341) compared with asymptomatic (n=146) patients (5.9 [interquartile range, 4.6-6.9] mg/dL versus 5.2 [interquartile range, 4.6-6.2] mg/dL; P=0.009). The current study supports a potential role of UA as a potential tissue participant and a systemic biomarker in the pathogenesis of carotid atherosclerosis. UA may provide a mechanistic explanation for plaque instability and subsequent ischemic cerebrovascular events.


TR1801-ADC: a highly potent cMet antibody-drug conjugate with high activity in patient-derived xenograft models of solid tumors.
cMet is a well-characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody-drug conjugates (ADCs). However, the clinical benefit from cMet-targeted therapy has been limited. We developed a novel cMet-targeted 'third-generation' ADC, TR1801-ADC, that was optimized at different levels including specificity, stability, toxin-linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site-specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin-linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet-expressing cell lines but also in medium-to-low cMet cell lines (40 000-90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low-medium cMet expression were also very responsive to TR1801-ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801-ADC had excellent efficacy with significant antitumor activity in 90% of tested patient-derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single-dose administration. Altogether, TR1801-ADC is a new generation cMet ADC with best-in-class preclinical efficacy and good tolerability in rats.