Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism.
Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.


Quality of life in geriatric generalized anxiety disorder: a preliminary investigation.
To examine the impact of late-life generalized anxiety disorder (GAD) on health-related quality of life. We compared quality of life in 75 treatment-seeking older adults with GAD, 39 of whom had psychiatric comorbidity, with 32 older adults without psychiatric illness. We examined predictors of quality of life in these samples. We also compared data from the GAD patients to published norms from a large national sample of older adults with chronic medical conditions or major depression. Older GAD patients reported worse health-related quality of life across most domains than asymptomatic older individuals. There were no differences in quality of life between GAD patients with and without psychiatric comorbidity, and comorbidity did not predict quality of life in multivariate regression analyses. Presence of GAD or symptoms of anxiety or depression were significantly related to impairment in every domain of quality of life. Comparisons with national norms suggest that older GAD patients report overall worse quality of life than individuals with recent acute myocardial infarction or type II diabetes, and are comparable in quality of life to individuals with major depression. Results suggest that late-life GAD is associated with substantial impairment in quality of life, and these findings cannot be explained by psychiatric comorbidity.


Intensive chemotherapy perturbs heart rate variability in children with cancer.
In children, cancer chemotherapy may impair the functioning of the cardiac autonomic nervous system. Moreover, it is not known whether there are any differences between intensive and maintenance phases of chemotherapy. Therefore, the aim of the current study was to assess autonomic nervous system activity using heart rate variability, in children receiving intensive or maintenance cancer chemotherapy. For that purpose, children who were healthy (healthy control, n = 30), receiving intensive chemotherapy (chemotherapy, n = 30), and receiving maintenance chemotherapy (maintenance, n = 25) were included in the study. Autonomic nervous system activity was measured by means of heart rate variability. Electrocardiogram recordings were used to calculate time- and frequency-domain heart rate variability parameters. Time-domain parameters such as standard deviation of NN intervals and frequency-domain parameters such as total power were lower during the intensive chemotherapy but not during maintenance phase (standard deviation of NN intervals: 50±5, 33±3, and 48±3 ms, and total power: 2613±504, 1379±296 and 2295±264 ms2, respectively for healthy control, chemotherapy and maintenance groups, P<0.001 for both standard deviation of NN intervals and total power). The present results indicate that intensive chemotherapy perturbs the function of heart rate variability in children, with recovery during the maintenance phase. This suggests that intensive chemotherapy is likely to affect the autonomic nervous system but this effect does not appear to be permanent.


Classical conditioning of motor responses: what is the learning mechanism?
According to a widely held assumption, the main mechanism underlying motor learning in the cerebellum, such as eyeblink conditioning, is long-term depression (LTD) of parallel fibre to Purkinje cell synapses. Here we review some recent physiological evidence from Purkinje cell recordings during conditioning with implications for models of conditioning. We argue that these data pose four major challenges to the LTD hypothesis of conditioning. (i) LTD cannot account for the pause in Purkinje cell firing that is believed to drive the conditioned blink. (ii) The temporal conditions conducive to LTD do not match those for eyeblink conditioning. (iii) LTD cannot readily account for the adaptive timing of the conditioned response. (iv) The data suggest that parallel fibre to Purkinje cell synapses are not depressed after learning a Purkinje cell CR. Models based on metabotropic glutamate receptors are also discussed and found to be incompatible with the recording data.


Involvement of the serotonergic system in orexin-induced behavioral alterations in rats.
We have demonstrated involvement of the serotonergic system in orexin-induced behavioral responses in rats. Orexin-A and -B (hypocretin-1 and -2) significantly increased total locomotor activity when administered centrally. They also induced behavioral alterations; increasing grooming, face washing and wet dog shaking in rats. Haloperidol inhibited orexin-induced hyperlocomotion and these behavioral alterations. Serotonin antagonists, ritanserin and metergoline, did not attenuate orexin-induced hyperlocomotion but partly inhibited orexin-induced behavioral alterations. These results suggest that the dopaminergic system might be involved in orexin-induced hyperlocomotion, while both the serotonergic system as well as the dopaminergic system might be involved in orexin-induced behavioral responses.


The Role of Inflammation in the Pathophysiology of Depression and Suicidal Behavior: Implications for Treatment.
Depression and suicidal behavior are 2 complex psychiatric conditions of significant public health concerns due to their debilitating nature. The need to enhance contemporary treatments and preventative approaches for these illnesses not only calls for distillation of current views on their pathogenesis but also provides an impetus for further elucidation of their novel etiological determinants. In this regard, inflammation has recently been recognized as a potentially important contributor to the development of depression and suicidal behavior. This review highlights key evidence that supports the presence of dysregulated neurometabolic and immunologic signaling and abnormal interaction with microbial species as putative etiological hallmarks of inflammation in depression as well as their contribution to the development of suicidal behavior. Furthermore, therapeutic insights addressing candidate mechanisms of pathological inflammation in these disorders are proposed.


Understanding the regulation of "Don't Eat-Me" signals by inflammatory signaling pathways in the tumor microenvironment for more effective therapy.
Receptor/ligand pair immune checkpoints are inhibitors that regulate immunity as vital "Don't Find-Me" signals to the adaptive immune system, additionally, the essential goals of anti-cancer therapy. Moreover, the immune checkpoints are involved in treatment resistance in cancer therapy. The immune checkpoints as a signal from "self" and their expression on healthy cells prevent phagocytosis. Cells (e.g., senescent and/or apoptotic cells) with low immune checkpoints, such as low CD47 and/or PD-L1, are phagocytosed, which is necessary for tissue integrity and homeostasis maintenance. In other words, cancer cells induce increased CD47 expression in the tumor microenvironment (TME), avoiding their clearance by immune cells. PD-L1 and/or CD47 expression tumors have also been employed as biomarkers to guide cure prospects. Thus, targeting innate and adaptive immune checkpoints might improve the influence of the treatments on tumor cells. However, the CD47 regulation in the TME stands intricate, so much of this process has stayed a riddle. In this line, less attention has been paid to cytokines in TME. Cytokines are significant regulators of tumor immune surveillance, and they do this by controlling the actions of the immune cell. Recently, it has been suggested that different types of cytokines at TME might cooperate with others that contribute to the regulation of CD47 and/or PD-L1. The data were searched in available databases and a Web Search engine (PubMed, Scopus, and Google Scholar) using related keywords in the title, abstract, and keywords. Given the significant role of pro/anti-inflammatory signaling in the TME, we discuss the present understanding of pro/anti-inflammatory signaling implications in "Don't Eat-Me" regulation signals, particularly CD47, in the pathophysiology of cancers and come up with innovative opinions for the clinical transformation and personalized medicine.


Adipocyte-derived kynurenine stimulates malignant transformation of mammary epithelial cells through the aryl hydrocarbon receptor.
Anti-hormone therapies are not efficacious for reducing the incidence of triple negative breast cancer (TNBC), which lacks both estrogen and progesterone receptors. While the etiology of this aggressive breast cancer subtype is unclear, visceral obesity is a strong risk factor for both pre- and post-menopausal cases. The mechanism by which excessive deposition of visceral adipose tissue (VAT) promotes the malignant transformation of hormone receptor-negative mammary epithelial cells is currently unknown. We developed a novel in vitro system of malignant transformation in which non-tumorigenic human breast epithelial cells (MCF-10A) grow in soft agar when cultured with factors released from VAT. These cells, which acquire the capacity for 3D growth, show elevated aryl hydrocarbon receptor (AhR) protein and AhR target genes, suggesting that AhR activity may drive malignant transformation by VAT. AhR is a ligand-dependent transcription factor that generates biological responses to exogenous carcinogens and to the endogenous tryptophan pathway metabolite, kynurenine. The serum kynurenine to tryptophan ratio has been shown to be elevated in patients with obesity. Herein, we demonstrate that AhR inhibitors or knockdown of AhR in MCF-10A cells prevents VAT-induced malignant transformation. Specifically, VAT-induced transformation is inhibited by Kyn-101, an inhibitor for the endogenous ligand binding site of AhR. Mass spectrometry analysis demonstrates that adipocytes metabolize tryptophan and release kynurenine, which is taken up by MCF-10A cells and activates the AhR to induce CYP1B1 and promote malignant transformation. This novel hormone receptor-independent mechanism of malignant transformation suggests targeting AhR for TNBC prevention in the context of visceral adiposity.


Active peptides from amphibian skin are also amphibian neuropeptides.
Immunohistochemical data on several newt brain areas showed a heterogeneous system of neuronal elements, immunopositive for antisera specifically directed to different antigenic determinants of tachykinin molecules. Acid extracts of newt brain areas were immunopositive for substance P with an antibody specific for the COOH-terminal (tachykinin determinant) and exhibits an elution profile by gel filtration characteristic to substance P. Bombesin-like immunoreactivity was demonstrable both by immunohistochemistry (fibers and cell bodies in forebrain and hypothalamic areas) and by radioimmunoassay, using an antiserum specific for the mid-region of the molecule. This immunoreactivity was separated into two peaks by gel filtration chromatography. Sauvagine-like material was detected by immunohistochemistry in newt hypothalamus as a loose preoptic cell system and as a thin fiber layer in the outer zone of the median eminence. Double staining procedures demonstrate that sauvagine and CRF are spatially closely related but separable in both the preoptic area and in the median eminence. This data on the presence of several amphibian skin peptides in the CNS of the newt suggests their possible role as neuropeptide.


AHNAK-modified microbubbles for the intracranial delivery of triptolide: In-vitro and in-vivo investigations.
Autophagic dysfunction related cascade events might induce the accumulation of α-synuclein (αSyn) in Parkinson's disease (PD). Triptolide (T10) has been reported as a potential autophagy inducer but limited by hepatotoxicity, low solubility and rapid metabolism. In this study, a novel AHNAK-targeted microbubbles integrated with T10 (T10-AHNAK-MBs) was developed to alleviate motor deficit in rAAV2/5-wild type and A53T mutant αSyn transfected PD mouse model. AHNAK facilitated the accumulation of microbubbles (MBs) near the cerebral vessel wall. Furthermore, bubble cavitation caused by focused-ultrasound (FUS) exposure could simultaneously induce drug release and blood-brain-barrier opening in the area of interest. The results of western blotting, thioflavin S staining, immunofluorescence, ELISA and behavior test demonstrated that T10-AHNAK-MBs with FUS exposure (T10-AHNAK-MBs-FUS) could significantly delivery more T10 into substantia nigra, promote clearance of various forms of αSyn, reduce tyrosine hydroxylase positive neuron loss, restore dopamine secretion, and eventually alleviate motor deficits, along with largely reduced adverse effects. The analyses of autophagic markers suggested that autophagy lysosome pathway (ALP) might dominate the T10-induced αSyn degeneration, including the oligomers and pre-formed fibrils. Thus, T10-AHNAK-MBs-FUS constitutes a promising strategy against the motor deficits in PD by promoting clearance of pathogenic αSyn aggregates via inducing ALP.


Pharmacokinetics of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine in patients with severe human immunodeficiency virus infection.
This article describes the pharmacokinetics of 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) as determined during phase I clinical trials in patients with acquired immunodeficiency syndrome and acquired immunodeficiency syndrome-related complex. Drug levels were determined by HPLC in plasma, cerebrospinal fluid, and urine after administration of the drugs either intravenously or as an oral liquid given with antacid. ddA was metabolized rapidly and quantitatively to ddI to such an extent that ddA was undetectable in the plasma even during continuous intravenous administration of ddA. The plasma kinetics of ddI were generally monoexponential and were characterized by a half-life of 38 minutes. This probably does not accurately reflect the kinetics of the active species of ddI, which appears to be 2',3'-dideoxyadenosine triphosphate, formed intracellularly. Oral bioavailability was 38% for oral liquid given with antacid. The total body clearance averaged 1.00 L/kg/hr, with a volume of distribution of 1.01 L/kg. Approximately 36% of the intravenous dose could be recovered unchanged in the urine. The level of ddI in the cerebrospinal fluid 1 hour after drug infusion averaged 21% of that of the simultaneous plasma level. It is concluded that ddI has pharmacokinetic properties that are amenable to its clinical use.


Sensitivity and Specificity of Emergency Physicians and Trainees for Identifying Internally Concealed Drug Packages on Abdominal Computed Tomography Scan: Do Lung Windows Improve Accuracy?
Suspected body packers may be brought to emergency departments (EDs) close to international airports for abdominal computed tomography (CT) scanning. Senior emergency clinicians may be asked to interpret these CT scans. Missing concealed drug packages have important clinical and forensic implications. The accuracy of emergency clinician interpretation of abdominal CT scans for concealed drugs is not known. Limited evidence suggests that accuracy for identification of concealed packages can be increased by viewing CT images on "lung window" settings. To determine the accuracy of senior emergency clinicians in interpreting abdominal CT scans for concealed drugs, and to determine if this accuracy was improved by viewing scans on both abdominal and lung window settings. Emergency clinicians blinded to all patient identifiers and the radiology report interpreted CT scans of suspected body packers using standard abdominal window settings and then with the addition of lung window settings. The reference standard was the radiologist's report. Fifty-five emergency clinicians reported 235 CT scans. The sensitivity, specificity, and accuracy of interpretation using abdominal windows was 89.9% (95% confidence interval [CI] 83.0-94.7), 81.9% (95% CI 73.7-88.4), and 86.0% (95% CI 81.5-90.4), respectively, and with both window settings was 94.1% (95% CI 88.3-97.6), 76.7% (95% CI 68.0-84.1), 85.5% (95% CI 81.0-90.0), respectively. Diagnostic accuracy was similar regardless of the clinician's experience. Interrater reliability was moderate (kappa 0.46). The accuracy of interpretation of abdominal CT scans performed for the purpose of detecting concealed drug packages by emergency clinicians is not high enough to safely discharge these patients from the ED. The use of lung windows improved sensitivity, but at the expense of specificity.


Variations in keratinizing odontogenic cysts and tumors.
Classification of keratinizing odontogenic cysts and tumors is not entirely satisfactory to the clinician and pathologist because many individual cases do not fit precisely into a particular category. This report describes the nature of some of these marginal lesions in order that similar cases may be diagnosed and treated correctly. Eight selected cases are described histologically, and their clinical behavior is discussed. It is concluded that the histopathologic appearance of the odontogenic epithelium in odontogenic cysts and tumors varies to a large extent and gives rise to a variety of keratinizing lesions. It is further concluded that some varieties are unique and, for the present, treatment of the rare lesions depends more on observed clinical behavior, with morphology having a lesser role in prognosis. It is important that clinicians as well as pathologists be aware of the wide variation of these keratinizing lesions so that the patient will receive optimum treatment.


The obese older female patient: CV risk and the SCOUT study.
Cardiovascular disease is a major killer in women yet is frequently considered a male-dominated disease. The risk of cardiovascular disease in women is frequently underestimated and there is also considerable evidence of a treatment bias against women. Women are generally underrepresented in cardiovascular clinical trials yet there is evidence of gender-specific differences in the responses to pharmacotherapy. The Sibutramine Cardiovascular Outcomes (SCOUT) trial has been designed to determine whether weight management with sibutramine together with a diet- and exercise-based lifestyle intervention can prevent cardiovascular morbidity and mortality in high-risk overweight and obese patients. The SCOUT population includes a large number of older women, at high risk for cardiovascular disease. Data from the trial's lead-in phase indicate that treatment with sibutramine and lifestyle management for 6 weeks result in clinically important weight loss and reduction in waist circumference. Despite an initial lower body weight, older women with cardiovascular disease and diabetes mellitus appear to lose as much weight as men. In the overall SCOUT population, treatment with sibutramine is associated with small median decreases in systolic and diastolic blood pressure and small median increases in pulse rate. The side-effect profile of sibutramine in this older, 'at-risk' population was similar to that previously observed in younger patients.


Prenatal methamphetamine attenuates serotonin mediated renin secretion in male and female rat progeny: evidence for selective long-term dysfunction of serotonin pathways in brain.
In adult rats, methamphetamine produces biochemical alterations in brain serotonin (5-HT) neurons. Since 5-HT is critical to the development of fetal 5-HT neurons and target tissues, we hypothesized that in utero exposure to methamphetamine could result in long-term alterations in postnatal 5-HT systems. Pregnant Sprague-Dawley rats, administered either saline or (+/-)methamphetamine (5 mg/kg, s.c., b.i.d.) from gestational day 13 to 20, were divided into three treatment groups: Saline-injected/Ad Lib Fed (VEH); Saline-injected/Pair Fed (PF); and methamphetamine injected (METH). Prenatal methamphetamine exposure did not alter litter size, gender number, or progeny birth weights. Functional alterations in serotonergic systems were determined in postnatal day (PD) 70 male progeny and in PD 30 female progeny by measuring changes in 5-HT mediated increases in plasma hormones following a single injection of the 5-HT releaser p-chloroamphetamine (PCA; 8 mg/kg). Prenatal methamphetamine produced long-term marked (-30 to -62%) attenuation of plasma renin responses to PCA in male and female progeny. In contrast, no alterations were observed in the ACTH, corticosterone, or prolactin responses to PCA in male and female progeny. Prenatal methamphetamine did not alter basal levels of any hormones measured regardless of gender. No significant differences were observed in the density of cortical or hypothalamic 5-HT uptake sites, or in the density of cortical 5-HT1 or 5-HT2 receptors in male progeny. The lack of significant differences in cortical 5-HT uptake sites observed between PF and METH treated dams 2 days post-parturition indicates that methamphetamine was not neurotoxic to the pregnant dams. These data, which demonstrate longterm postnatal deficits in 5-HT mediated renin secretion, suggest selective functional alterations of brain 5-HT systems in male and female progeny exposed in utero to methamphetamine.


Pathogenesis of Hobbs' heat-sensitive spore forming Clostridium perfringens type A strain.
Food poisoning in man due to heat-sensitive strains of Cl. perfringens type A appeared to be mediated through enterotoxin synthesized in vivo during sporulation. A minimum of 2.0 X 10(5) vegetative cells suspended in sporulation medium was sufficient to elicit gut-loop response in rabbits. The functional disturbance in the gut as well as the structural changes were progressive and proportional to the size of the inoculum up to a dose limit of 2.0 X 10(7) vegetative cells and beyond this the changes remained steady.


Effect of insulin therapy on endothelium-dependent dilation in type 2 diabetes mellitus.
Endothelial dysfunction is an early marker of atherosclerosis occurring in patients with type 2 diabetes mellitus. Endothelium-dependent dilation (EDD) has been shown to improve by combined therapy of insulin and metformin. Studies on endothelium-independent vasodilatory capacity, however, have had controversial results. We sought to investigate the vascular reactivity--EDD and endothelium-independent dilation--and their changes induced by the addition of insulin therapy to patients with type 2 diabetes mellitus pretreated with diet and oral hypoglycemic drugs. We therefore performed vascular studies in 21 poorly controlled type 2 diabetic patients and 11 nondiabetic control subjects by using high resolution ultrasound of the brachial artery. After 3 months of additional insulin therapy, vascular and laboratory measurements including C-reactive protein and parameters of glucose and lipoprotein metabolism were repeated. At baseline, EDD was significantly impaired in diabetic patients compared with controls (2.7 +/- 2.2% vs 7.0 +/- 1.8%, p <0.001), whereas endothelium-independent dilation was normal in both groups. After insulin therapy, EDD increased from 2.7 +/- 2.2% to 5.0 +/- 2.8% (p <0.001) in diabetic patients. All other vascular parameters did not change over the treatment period. The absolute change in EDD showed a significant negative correlation with the change in hemoglobin A(1c) (r = -0.67, p <0.001) and with fasting blood glucose (r = -0.84, p <0.001) levels. In contrast, there was no correlation between EDD and the observed changes in lipid and C-reactive protein levels. Our findings demonstrate that insulin therapy has beneficial effects on vascular function, resulting in enhanced EDD, most probably due to an improved glycemic control as the underlying mechanism.


Defective antioxidant systems in cervical cancer.
Cervical cancer remains a great problem for woman health, as it is the second deadly cancer of females worldwide. The infection of human papilloma virus (HPV) is the major risk factor for this cancer, although several other factors are also associated. Oxidative stress or antioxidant deficiency has been frequently identified to be associated with cervical cancer. Defects in the antioxidant enzyme systems are reported to play important role behind this antioxidant deficiency, which is responsible for the production of reactive oxygen species and ultimately, DNA damage in cervical cells. In response, cells become more vulnerable to HPV infection for cervical cancer development. Recently, antioxidant therapies or dietary supplementation of antioxidants have gained considerable interests in the cervical cancer treatment. In this study, we have reviewed the association of defective antioxidant systems and cervical cancer development. The recent advances in both of the basic and clinical research focusing on possible antioxidant therapy have also been discussed.


Blood glucose levels in neonatal sepsis and probable sepsis and its association with mortality.
To determine the blood glucose levels among patients with neonatal sepsis and probable sepsis and evaluate their association with the mortality rate. Analytical study. Fazle Omar Hospital, Rabwah, Pakistan from July 2007 to December 2008. Neonates with culture proven and probable neonatal sepsis were included. The glucose levels at the time of admission and outcomes were recorded. The patients were divided in four groups according to their glucose levels i.e. < 40 mg/dl, 40-100 mg/dl, 101-200 mg/dl and > 200 mg/dl. The patients were divided in two groups according to weight i.e. < 2.5 kg and ³ 2.5 kg. There were a total of 502 cases. The glucose levels were below 40 mg/dl in 50 patients (9.9%), between 40 mg/dl to 100 mg/dl in 322 (64.1%), between 101 mg/dl to 200 mg/dl in 95 (18.9%) and above 200 mg/dl in 35 patients (6.9%). Among these four groups, 16 (32%), 32 (9.9%), 22 (23.2%) and 17 (48.6%) neonates died respectively (p < 0.001). The difference in glucose levels among the two groups according to weight was significant (p=0.002). Majority of patients with neonatal sepsis and probable sepsis had glucose levels between 40 and 100 mg/dl at admission. Those with the levels below 40 mg/dl and above 200 mg/dl had higher mortality rates.


Field trial of the Global Assessment of Functioning Scale--Modified.
A field trial of the Global Assessment of Functioning Scale--Modified was conducted to test its construct validity. A slightly altered form of the scale, the Social and Occupational Functioning Assessment Scale, was used in DSM-IV. Social, occupational, and clinical data on 196 subjects receiving outpatient mental health services were analyzed. Six significant predictors were found that accounted for 51.75% of the variation in scores on the Global Assessment of Functioning Scale--Modified. Scores were independent of axis I, axis II, and psychoactive substance dependence diagnoses from DSM-III-R. The construct validity of the Global Assessment of Functioning Scale--Modified and the Social and Occupational Functioning Assessment Scale is supported by these findings.


Swelling-strengthening hydrogels by embedding with deformable nanobarriers.
Biological tissues, such as muscle, can increase their mechanical strength after swelling due to the existence of many biological membrane barriers that can regulate the transmembrane transport of water molecules and ions. Oppositely, typical synthetic materials show a swelling-weakening behavior, which always suffers from a sharp decline in mechanical strength after swelling, because of the dilution of the network. Here, we describe a swelling-strengthening phenomenon of polymer materials achieved by a bioinspired strategy. Liposomal membrane nanobarriers are covalently embedded in a crosslinked network to regulate transmembrane transport. After swelling, the stretched network deforms the liposomes and subsequently initiates the transmembrane diffusion of the encapsulated molecules that can trigger the formation of a new network from the preloaded precursor. Thanks to the tough nature of the double-network structure, the swelling-strengthening phenomenon is achieved to polymer hydrogels successfully. Swelling-triggered self-strengthening enables the development of various dynamic materials.


Differential levels of thyroid peroxidase and thyroglobulin messenger ribonucleic acids in congenital goiter with defective thyroglobulin synthesis.
The biosynthesis of thyroid hormones requires iodide, thyroid peroxidase (TPO), thyroglobulin (Tg) and H2O2. We have studied two sisters with congenital large goiters and hypothyroidism. Perchlorate tests were negative. Serum T3 and T4 were decreased, TSH was increased and Tg was within the lower limit of normal. Biochemical and molecular studies were performed on goiter samples obtained after surgery. Tg content in both tissues was negligible. Paper chromatography of labeled iodocompounds showed a decrease in T4, and the presence of a pronase/pancreatin-resistant iodoprotein. TPO activity was normal in the tissues. Sephacryl S-300 gel filtration demonstrated labeled iodoalbumin-like protein and the absence of a Tg peak. Salting out studies of soluble protein fraction gave an abnormal pattern. Agarose gel electrophoresis showed the presence of an iodoalbumin-like protein and the absence of Tg in the tissues. This last finding was confirmed by immunoelectrophoresis. The Tg and TPO mRNAs levels were also analyzed. Dot-blot hybridization studies with pM5 (TPO cDNA) and phTgM2 (Tg cDNA) probes showed increased and decreased signals, respectively. The increase in TPO mRNA can be explained as a compensatory mechanism vis a vis an increase in serum TSH caused by decreased serum T3 and T4 due to the impairment in Tg mRNA. The Tg mRNA of both patients was further studied with four different probes covering 5' and 3' regions (phTgM1, phTgB1, phTgB2 and phTgB3). Hybridization was observed with all four probes, thus excluding a dramatic deletion defect. Northern transfer showed a clear signal of hybridization with the phTgB1 probe in the 8-9 Kb range. We may conclude that the biochemical and molecular abnormality of these patients is characterized by a decrease of Tg mRNA and of Tg translation.


Feasibility and Safety of Diffusing Alpha-Emitter Radiation Therapy for Recurrent or Unresectable Skin Cancers.
Patients with recurrent or unresectable skin cancers have limited treatment options. Diffusing alpha-emitter radiation therapy (DaRT), a novel solid tumor management strategy using alpha-particle interstitial brachytherapy, may address this challenge. To evaluate the feasibility and safety of using DaRT to manage recurrent or unresectable skin cancers. This prospective cohort study of patients who received a 2-week to 3-week treatment course and were followed up for 24 weeks after treatment during 2021 and 2022 at 2 sites in the US. Patients with malignant skin tumors or soft tissue tumors were recruited if they had limited treatment options for tumors recurrent after prior surgery or external beam radiotherapy or unresectable tumors. Patients underwent DaRT to deliver a physical dose of 10 Gy (equivalent weighted dose of 200 CGE) to the tumor. Feasibility of the DaRT procedure was evaluated based on the ability of investigators to successfully deliver radiation to the tumor. Patients were followed up for adverse events (AEs) for 24 weeks and for tumor response by physicians' physical examination and imaging 12 weeks after device removal. This study included 10 participants with recurrent or unresectable skin cancer (median [IQR] age, 72 [68-75] years; 6 males [60%]; 4 females [40%]). Six patients (60%) had recurrent disease, and 4 (40%) had tumors that were deemed unresectable. Tumors were located on the nose, chin, eyelid, scalp, neck, trunk, and extremities. Median (range) tumor volume before treatment was 2.1 cm3 (0.65-12.65 cm3). The mean (SD) prescription dose coverage of the gross tumor volume was 91% (2.8%) with all tumors having coverage of 85% or more. No device-related grade 3 AEs were noted. Common AEs were grade 1 to 2 erythema, edema, and pruritus. At 12 weeks following treatment, there was a 100% complete response rate. Nine of 10 complete responses (90%) were confirmed by CT imaging. This cohort study suggests the feasibility and preliminary safety of DaRT in the management of recurrent or unresectable skin cancers. The favorable safety profile and high response rates are promising. A US trial for marketing approval based on this pilot study is under way. ClinicalTrials.gov Identifier: NCT04377360.


Estrone sulfatase activity in patients with advanced ovarian cancer.
We sought to identify whether the sulfatase pathway was present in ovarian cancer specimens and then to determine whether a clinical correlation existed between sulfatase activity and survival. Enzymatic activity was assessed in advanced ovarian cancer specimens via thin layer chromatography and standardized against total protein. All enzyme activities are reported in pmol/mg protein/30 min. Kaplan Meier curves of progression-free and overall survival were constructed to compare outcomes between patients with low sulfatase activity and high sulfatase activity. Median survival rates were compared using the log-rank test for survival curves. Differences in proportions between patients with low sulfatase activity versus high sulfatase activity were compared with the z-test or chi-square analysis as appropriate. 37 specimens from patients with advanced stage ovarian cancer were analyzed. Enzymatic activity was detected in all specimens except one. Median progression-free survival was 23.5 months for patients with low sulfatase activity compared to 6.9 months for patients with high sulfatase activity (p=0.008). Median overall survival favored the low sulfatase group (50.8 vs. 30.6 months respectively), though statistical difference was not detected (p=0.16). No other difference in clinical characteristics between patients with high or low sulfatase activity was detected. Sulfatase activity is widely present in ovarian cancer specimens. Increased sulfatase activity is associated with worse progression-free survival in patients with advanced stage ovarian cancer. The sulfatase pathway is a potential therapeutic target in the treatment of ovarian cancer.


Influence of sunflecks on the temperature and water relations of two subalpine understory congeners.
The temperature and water relations of the herbaceous, understory, congeners Arnica cordifolia and Arnica latifolia were evaluated in relation to the sunfleck dynamics of their respective microhabitats. Arnica cordifolia microhabitats had more frequent, longer, and more intense sunflecks than those of A. latifolia which led to higher leaf temperatures (31°C versus 15°C) and transpirational fluxes (65 μg cm-2 s-1 versus 16 μg cm-2 s-1). Stomatal closure did not occur in response to high leaf temperatures and low stem water potentials during natural sunfleck exposures, even though plants were observed to wilt during midday, especially A. cordifolia. Experimentally, an artificial midday sunfleck of about 165 min caused plants of A. cordifolia not to regain turgor after 8 h in shade compared to a sunfleck duration of about 90 min for plants of A. latifolia. However, these sunfleck intervals occurred naturally only during the early morning and late afternoon when solar intensities were minimal. Also, A. cordifolia populations had over twice as many plants that were sunlit (>40% of total) compared with A. latifolia (<20% of total) at any particular time during a day. The small-scale distribution of both species appears tightly coupled to the sunfleck dynamics of their respective microhabitats due to the lack of stomatal action which would reduce transpiration and improve plant water status under sunlit conditions.


Recombinant AAV serotype and capsid mutant comparison for pulmonary gene transfer of alpha-1-antitrypsin using invasive and noninvasive delivery.
Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The noninvasive intranasal delivery was compared with the traditional intratracheal lung delivery. The rAAV8 was the most efficient serotype at expressing alpha-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 x 10(10) vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar lavage fluid (BALF) levels of human AAT (hAAT) were about 6- and 2.5-fold higher, respectively, than those of rAAV5 group. Among the rAAV2 capsid mutants, the rAAV2 capsid mutants that display a peptide sequence from hAAT ("long serpin") indicated a twofold increase in transgene expression. For most vectors, the serum hAAT levels achieved after intranasal delivery were 1/2 to 1/3 of those with the intratracheal method. Overall, rAAV8 was the most promising vector for the future application in gene therapy of pulmonary diseases such as AAT deficiency-related emphysema.


Conjoined twins pregnancies: experience with 36 cases from a single center.
To review a single center's experience in the management of twin pregnancies with conjoined fetuses. Retrospective study describing prenatal findings, delivery details, surgical treatment and perinatal outcome. The study included 36 twin pregnancies with conjoined twins seen over a period of 12 years in a single tertiary hospital: 69.4% were thoracopagus, 13.9% parapagus, 8.3% omphaloischiopagus 5.6% omphalopagus and 2.8% cephalopagus. Cardiac defects were present in 91.6% of twin pairs and associated malformations were present in 61.8% of the cases: limb abnormalities in 36.1%, abdominal wall defects in 25.0%, cleft lip and/or palate in 13.9% and congenital diaphragmatic hernia in 5.5%. Surgical separation was considered not feasible and prognosis lethal in 30 (83.3%) cases. Termination of pregnancy was performed in 12 pregnancies of poor prognosis. Cesarean section was performed in all remaining cases. Five sets of twins underwent surgical separation and six children survived. Overall survival in our series was 8.3% and, among the livebirths, 13.6%. Conjoined twin pregnancies should be referred to tertiary centers for detailed fetal anomaly and echocardiographic assessment to evaluate prognosis and determine the possibility of postnatal surgical separation.


Tetraethylammonium ion sensitivity of a 35-pS CA2(+)-activated K+ channel in GH3 cells that is activated by thyrotropin-releasing hormone.
Single Ca2(+)-activated K+ channels were studied in membrane patches from the GH3 anterior pituitary cell line. We have previously demonstrated the coexistence of large-conductance and small-conductance (280 pS and 11 pS in symmetrical 150 mM K+, respectively) Ca2(+)-activated K+ channels in this cell line (Lang and Ritchie 1987). Here we report the existence of a third type of Ca2(+)-activated K+ channel that has a conductance of about 35 pS under similar conditions. In excised inside-out patches, this channel can be activated by elevations of the internal free Ca2+ concentration, and the open probability increases as the membrane potential is made more positive. In excised patches, the sensitivity of this 35-pS channel to internal Ca2+ is low; at positive membrane potentials, this channel requires Ca2+ concentrations greater than 10 microM for activation. However, 35-pS channels have a much higher sensitivity to Ca2+ in the first minute after excision (activated by 1 microM Ca2+ at -50 mV). Therefore, it is possible that the Ca2+ sensitivity of this channel is stabilized by intracellular factors. In cell-attached patches, this intermediate conductance channel can be activated (at negative membrane potentials) by thyrotropin-releasing hormone-induced elevations of the intracellular Ca2+ concentration and by Ca2+ influx during action potentials. The intermediate conductance channel is inhibited by high concentrations of external tetraethylammonium ions (Kd = 17 mM) and is relatively resistant to inhibition by apamin.


Speaking a Different Language: A Qualitative Analysis Comparing Language of Palliative Care and Pediatric Intensive Care Unit Physicians.
Family conferences in the pediatric intensive care unit (ICU) often include palliative care (PC) providers. We do not know how ICU communication differs when the PC team is present. To compare language used by PC team and ICU physicians during family conferences. A retrospective cohort review of ICU family conferences with and without the PC team. Forty-four bed pediatric ICU in a tertiary medical center. Nine ICU physicians and 4 PC providers who participated in 18 audio-recorded family conferences. Of the 9 transcripts without the PC team, we identified 526 ICU physician statements, generating 10 thematic categories. The most common themes were giving medical information and discussing medical options. Themes unique to ICU physicians included statements of hopelessness, insensitivity, and "health-care provider challenges." Among the 9 transcripts with the PC team, there were 280 statements, generating 10 thematic categories. Most commonly, the PC team offered statements of support, giving medical information, and quality of life. Both teams promoted family engagement by soliciting questions; however, the PC team was more likely to use open-ended questions, offer support, and discuss quality of life. Pediatric ICU physicians spend more time giving medical information, whereas the PC team more commonly offers emotional support. The addition of the PC team to ICU family conferences may provide a balanced approach to communication.


Reward Versus Nonreward Sensitivity of the Medial Versus Lateral Orbitofrontal Cortex Relates to the Severity of Depressive Symptoms.
The orbitofrontal cortex (OFC) is implicated in depression. The hypothesis investigated was whether the OFC sensitivity to reward and nonreward is related to the severity of depressive symptoms. Activations in the monetary incentive delay task were measured in the IMAGEN cohort at ages 14 years (n = 1877) and 19 years (n = 1140) with a longitudinal design. Clinically relevant subgroups were compared at ages 19 (high-severity group: n = 116; low-severity group: n = 206) and 14. The medial OFC exhibited graded activation increases to reward, and the lateral OFC had graded activation increases to nonreward. In this general population, the medial and lateral OFC activations were associated with concurrent depressive symptoms at both ages 14 and 19 years. In a stratified high-severity depressive symptom group versus control group comparison, the lateral OFC showed greater sensitivity for the magnitudes of activations related to nonreward in the high-severity group at age 19 (p = .027), and the medial OFC showed decreased sensitivity to the reward magnitudes in the high-severity group at both ages 14 (p = .002) and 19 (p = .002). In a longitudinal design, there was greater sensitivity to nonreward of the lateral OFC at age 14 for those who exhibited high depressive symptom severity later at age 19 (p = .003). Activations in the lateral OFC relate to sensitivity to not winning, were associated with high depressive symptom scores, and at age 14 predicted the depressive symptoms at ages 16 and 19. Activations in the medial OFC were related to sensitivity to winning, and reduced reward sensitivity was associated with concurrent high depressive symptom scores.


Secretory immunoglobulin A in the human endolymphatic sac. An immunohistochemical study.
Presence of immunoglobulin A (IgA) and of secretory component in epithelial cells and in the lumen of the human endolymphatic sac was demonstrated by two different immunohistochemical methods. IgA was also detected in perisaccular plasma cells. The findings connote the existence of a local immune system of the inner ear.


Cdr1p highlights the role of the non-hydrolytic ATP-binding site in driving drug translocation in asymmetric ABC pumps.
ATP-binding cassette (ABC) transporters couple ATP binding and hydrolysis to the translocation of allocrites across membranes. Two shared nucleotide-binding sites (NBS) participate in this cycle. In asymmetric ABC pumps, only one of them hydrolyzes ATP, and the functional role of the other remains unclear. Using a drug-based selection strategy on the transport-deficient mutant L529A in the transmembrane domain of the Candida albicans pump Cdr1p; we identified a spontaneous secondary mutation restoring drug-translocation. The compensatory mutation Q1005H was mapped 60 Å away, precisely in the ABC signature sequence of the non-hydrolytic NBS. The same was observed in the homolog Cdr2p. Both the mutant and suppressor proteins remained ATPase active, but remarkably, the single Q1005H mutant displayed a two-fold reduced ATPase activity and a two-fold increased drug-resistance as compared to the wild-type protein, pointing at a direct control of the non-hydrolytic NBS in substrate-translocation through ATP binding in asymmetric ABC pumps.


Arterial flow in the lower leg correlated with plasma levels of two formulations of papaverine hydrochloride.
In patients with severe peripheral vascular disease (mean arterial flow of 40 ml/min), a suspension of papaverine in a soft gelatin capsule produced plasma levels almost three times higher than those following treatment with a sustained-release tablet formulation. The higher plasma levels resulted in significantly greater vasodilation with increased distal arterial flow. The onset of peak pulsatile flow with the soft gelatin form came sooner than with the sustained-release form. However the durations of vasodilation were similar with both papaverine preparations. The vasodilatory activity of papaverine appeared to be greater in the sympathectomized leg. The soft gelatin formulation of papter reconstruction of a large artery, and may be effective in sustaining a longer vasodilatory effect in patients with small vessel disease, when surgical procedures may not be applicable.


A STUDY ON TREATMENT OF CHRONIC IDIOPATHIC URTICARIA WITH CETIRIZINE.
In a prospective study a comparison has been made between the clinical efficacy and safety of cetirizine, a third generation H1 receptor antagonist with chlorpheniramine and cyprohepatadine, the most widely used antithistamines in the treatment of chronic idiopathic urticaria. One hundred and five patients with chronic idiopathic urticaria were studied where the effects of chlorpheniramine, 4 mg and cyproheptadine, 4 mg administered twice daily were compared with cetirizine, 10 mg given once daily for 4 weeks or earlier till the relief of symptoms and regression of lesions. Local therapy consisted of calamine lotion in all cases. Out of 35 patients receiving chlorpheniramine excellent response was achieved in 9 (25.7%) cases by subjective evaluation (SE) and 11 (31.4%) by objective evaluation (OE). Out of 35 cases, 7 (20%) and 10 (28.5%) cases treated with cyproheptadine have shown excellent response by SE and OE respectively. Out of 35 patients taking cetirizine 25 (71.4%) had shown excellent response by SE and 22 (62.8%) cases by OE. Drowsiness was an important side effect observed in 19 (54.2%) cases receiving chlorpheniramine, 22 (62.8%) patients taking cyproheptadine and 1 (2.8%) case getting cetirizine. These results suggest that cetirizine has got superior antiallergic activity than chlorpheniramine and cyproheptadine in the treatment of chronic idiopathic urticaria.


Easier, Better, Faster, Stronger: Improved Methods for RNA-Protein Interaction Studies.
The RNA field has been revolutionized by methods that allow genome-scale identification of RNA-protein interaction sites. Two reports now introduce more efficient approaches, opening the technology to wider adoption (Van Nostrand et al., 2016; Zarnegar et al., 2016).


Changes in cytokine signaling and extracellular matrix production induced by inflammatory factors in cultured vocal fold fibroblasts.
Modulating cytokine signaling in vocal fold fibroblasts after injury may influence extracellular matrix (ECM) production and eventual fibrotic outcome. To evaluate previously established in vivo cytokine and ECM gene expression hypotheses, we examined in vitro vocal fold fibroblast responses to exogenous inflammatory factor stimulation. Rat vocal fold fibroblast lines derived from explants were separately treated with interleukin-13 (IL-13), interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta subtype 1 (TGF-beta1), or prostaglandin E2 (PGE2). We examined the in vitro messenger RNA expression profiles of IL-1beta, IFN-gamma, TNF-alpha, TGF-beta1, and cyclooxygenase 2 (COX-2), as well as those of hyaluronic acid synthase (HAS) 1, HAS-2, procollagen subtype 1, and procollagen subtype 3, at 1,4, 8, 16, 24, and 72 hours after treatment, and compared them to those of untreated fibroblasts and in vivo data, using real-time reverse transcription-polymerase chain reaction. IL-1beta and TNF-alpha induced each other and synergistically increased HAS-1 and HAS-2 expression. PGE2 also up-regulated HAS-1 and HAS-2 expression. IFN-gamma, IL-1beta, TNF-alpha, and TGF-beta1 up-regulated HAS expression alongside either transient up-regulation of, or no change in, procollagen 1 and 3 expression. Most treatments appeared to suppress procollagen expression, possibly through HAS up-regulation. All inflammatory factors attenuated TGF-beta1 expression. These results confirm several in vivo trends, identify potential cytokine pathways and therapeutic candidates, and suggest the utility of this in vitro setup for future studies.


Trends in the epidemiology of childhood nephrotic syndrome in Africa: A systematic review.
Childhood nephrotic syndrome, if left untreated, leads to progressive kidney disease or death. We quantified the prevalence of steroid-sensitive nephrotic syndrome, steroid-resistant nephrotic syndrome, and histological types as the epidemiology of nephrotic syndrome in Africa remains unknown, yet impacts outcomes. We searched MEDLINE, Embase, African Journals Online, and WHO Global Health Library for articles in any language reporting on childhood nephrotic syndrome in Africa from January 1, 1946 to July 1, 2020. Primary outcomes included steroid response, biopsy defined minimal change disease, and focal segmental glomerulosclerosis (FSGS) by both pooled and individual proportions across regions and overall. There were 81 papers from 17 countries included. Majority of 8131 children were steroid-sensitive (64% [95% CI: 63-66%]) and the remaining were steroid-resistant (34% [95% CI: 33-35%]). Of children biopsied, pathological findings were 38% [95% CI: 36-40%] minimal change, 24% [95% CI: 22-25%] FSGS, and 38% [95% CI: 36-40%] secondary causes of nephrotic syndrome. Few African countries reported on the prevalence of childhood nephrotic syndrome. Steroid-sensitive disease is more common than steroid-resistant disease although prevalence of steroid-resistant nephrotic syndrome is higher than reported globally. Pathology findings suggest minimal change and secondary causes are common. Scarcity of data in Africa prevents appropriate healthcare resource allocation to diagnose and treat this treatable childhood kidney disease to prevent poor health outcomes. Funding was provided by the Canadian Institute for Health Research (CIHR) and the National Institute of Health (NIH) for the H3 Africa Kidney Disease Research Network. This research was undertaken, in part, from the Canada Research Chairs program.


L-Arginine inhibiting pulmonary vascular remodelling is associated with promotion of apoptosis in pulmonary arterioles smooth muscle cells in broilers.
Pulmonary vascular remodelling is one of the important pathological bases of broiler pulmonary hypertension syndrome (PHS). Nitric oxide (NO) has been found to inhibit proliferation and to induce apoptosis in pulmonary artery smooth muscle cells (SMC) in mammals with pulmonary hypertension. The present study was conducted to evaluate the effects of NO precursor l-arginine on pulmonary vascular remodelling in broilers with pulmonary hypertension induced by cold exposure and to examine whether NO-induced apoptosis in pulmonary arteriole SMC is involved in the regulatory mechanisms. Two hundred and forty mixed-sex commercial broilers were equally assigned to three groups and reared in normal brooding temperatures before day 14. Starting on day 14 continuing until the end of the experiment, the control group was brooded in normal temperatures whereas the other two groups were subjected to low ambient temperatures with or without l-arginine added to the basal diets. Cumulative PHS mortality and body weight were recorded in each group. Right/total ventricle ratio (RV/TV), plasma NO concentration and pulmonary vascular morphological changes were analyzed. TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay was used to detect apoptosis in pulmonary arteriole SMC. l-Arginine, in group A, had no effect on body weights under cold temperature condition. Birds kept in group B had increased PHS mortality, RV/TV ratio, vessel wall area/vessel total area ratios (WA/TA) and mean media thickness in pulmonary arterioles (mMTPA) (P<0.05). Percentages of apoptotic SMC in pulmonary arterioles in group B were not altered by cold exposure (P>0.05). Supplemental dietary l-arginine in group A elevated plasma NO level (P<0.05), reduced PHS mortality (P<0.05), attenuated pulmonary vascular remodelling and increased the percentages of apoptotic SMC (P<0.05) when compared with the group B. Supplemental l-arginine partially inhibited pulmonary vascular remodelling that occurred secondary to increased pulmonary pressure; NO-induced apoptosis in arteriole SMC might contribute to its regulatory effect on pulmonary vascular structural changes.


Does the "pacemaker current" generate the diastolic depolarization in the rabbit SA node cells?
Small preparations of spontaneously beating rabbit sino-atrial node (SA node) were voltage clamped with the two-microelectrode technique. The effects of 0.25-5 mM Cs+ on the spontaneous pacing rate and the time-dependent inward "pacemaker" current, ih, were studied. In the presence of 2 mM Cs+, the spontaneous pacing rate decreased only slightly even though ih was strongly depressed at potentials negative to -60 mV Cs+ had little or no effect on other time-dependent currents observed with clamp pulses less negative than -50 mV. Since no voltage-dependence to the Cs+ effect on ih could be measured (between -90 mV and -20 mV), it was considered unlikely that the lack of Cs+ effect on the rate of diastolic depolarization results from a voltage-dependent effect of Cs+ on the ih channel. Adrenaline produced a marked positive chronotropic effect in Cs+-treated SA node cells. This effect was accompanied by marked enhancement of the slow inward current (isi) with no change in the Cs+-blocked ih current. These results are consistent with the idea that ih plays a minor role in generation of pacemaker depolarization, and suggest a more prominent role of isi in the generation of diastolic depolarization in SA nodal cells.


Exercise and Dairy Protein have Distinct Effects on Indices of Liver and Systemic Lipid Metabolism.
This study aimed to explore the individual and combined effects of skim milk powder (SMP) and exercise on indices of systemic and liver lipid metabolism in male obese rats. Rats were fed a high-fat (~ 40% kcal from fat), high-sugar diet for 8 weeks. At 12 weeks of age, rats were assigned to one of four weight-matched, isocaloric, high-fat, high-sugar groups for 6 weeks: (1) casein-sedentary, (2) casein-exercise, (3) SMP-sedentary, and (4) SMP-exercise. Nonfat SMP or casein was the sole protein source in the dairy and control casein diets, respectively. Exercise training occurred 5 d/wk for 60 minutes on a motorized treadmill. Whole-body metabolism was assessed by a Comprehensive Lab Animal Monitoring System. Lipidomics, Western blot, and polymerase chain reaction were used to assess markers of hepatic lipid metabolism. Exercise, but not SMP, altered the fatty acid composition of liver triglycerides, reduced indices of lipogenesis, and increased expression of genes linked to oxidative metabolism, in conjunction with increases in whole-body fat oxidation. SMP and exercise reduced plasma triglycerides in an additive manner. These findings provide evidence that SMP and exercise exert distinct effects on whole-body and hepatic carbohydrate and lipid metabolism and that they could work in a synergistic manner to reduce serum triglyceride concentrations.


Botanical dietary supplements and the treatment of diabetes: what is the evidence?
With the increase in cases of diabetes, many patients are using dietary supplements in an attempt to improve diabetes control. It is estimated that one third of patients with diabetes use some type of dietary supplement or complementary and alternative medicine treatment. Dietary supplements have active pharmacologic ingredients that are not only responsible for their theorized mechanisms in lowering blood glucose, but that are also responsible for adverse effects and drug interactions. Clinicians and patients alike should be aware of which botanical products are currently being used in diabetes care and what adverse effects and monitoring parameters should be considered.


Feasibility of a Multicomponent Program to Promote Physical Activity and Nutrition in Georgia Low-Income Early Care and Education Settings.
This article describes the process and intermediate outcomes from a program implemented in 65 Early Care and Education (ECE) centers serving low-income families throughout Georgia during the 2014-2017 school years. The HealthMPowers' Empowering Healthy Choices in Schools, Homes, and Communities ECE program was based on the organization's previously successful elementary school program and aligns with current early childhood nutrition and physical activity recommendations. Participating centers worked with HealthMPowers for up to 3 years. A team from each center led changes by conducting annual self-assessments, creating and implementing improvement plans, and implementing nutrition and physical activity programs using educational resources and environmental cues. A monitoring and evaluation plan provided ongoing feedback to HealthMPowers and centers. Family and staff surveys provided insights into behaviors of children, families, and staff. Process measures included specific benchmarks (e.g., center leadership team formation, improvement plan implementation). Annual self-assessment results served as intermediate outcome measures. As of 2017, 65 centers had enrolled in the program. All centers formed a health team and completed the baseline self-assessment and most implemented an improvement plan (88%). At the 1-year follow-up self-assessment, centers reported improvements from baseline including never offering food incentives for good behavior (75%-86%), conducting taste testing at least once a month (61%-79%), and rarely/never serving sugar-sweetened beverages (93%-96%). Initial process measures from a multicomponent health promotion program in ECE were promising. An integrated continuous improvement approach to working with child care settings is feasible and likely effective.


Total hysterectomy for a nonprolapsed, benign uterus in women without vaginal deliveries.
To compare the different techniques of hysterectomy for a nonprolapsed, benign uterus in women without vaginal deliveries. A retrospective study in a university hospital analyzed 148 total hysterectomies in women without vaginal deliveries performed from August 1991 to June 2000. Forty-four patients had had cesarean sections (29.7%), and 104 (70.3%) were nulliparous. Twenty-four patients had had abdominal myomectomies (16.2%). The vaginal route (group 1) was used for 77 patients (52%), 56 (37.8%) had laparotomies (group 2), and 15 (10.2%) had laparoscopically assisted vaginal hysterectomies (group 3). The uterine weight was 275 (+/- SD 140) g in group 1, 830 (+/- SD 1620) in group 2 and 331 (+/- SD 160) in group 3. Mean operation time was 87 (+/- SD 76) minutes in group 1, 96 (+/- SD 41) in group 2 and 112 (+/- SD 56) in group 3. There was one serious complication with the vaginal route (sigmoid injury). The hospital stay was 4 (+/- SD 3.1) days in group 1, 7.1 (+/- SD 3.8) in group 2 and 4.3 (+/- SD 1.5) in group 3. Vaginal hysterectomy for a nonprolapsed, benign uterus is indicated for women without vaginal deliveries and is feasible in 72% of cases in our recent experience, with a low complication rate. Training in vaginal surgery should allow safe performance of the procedure at most centers.


A Pilot Randomized Controlled Trial of a Computer-Delivered Brief Intervention for Substance Use and Risky Sex During Pregnancy.
Sexually transmitted infections (STIs) are an increasingly critical and costly health problem for American childbearing women. Pregnant women who misuse substances are more likely to engage in risky sexual behavior that leads to STIs. Substance use and risky sex during pregnancy are both associated with numerous negative consequences for the woman and the developing fetus. A two-group, randomized controlled trial. Recruitment of 50 pregnant women (30% Latina; 24.4 years old [SD = 5.31]) with an average of 13 weeks gestation (SD = 4.5 weeks) was conducted at a prenatal clinic in a large inner-city hospital. Recruitment took place between 2015 and 2016, and data analysis took place in 2016. A computer-delivered, single-session brief motivational intervention plus booster session addressing both substance use and STI risk. To assess participants' perceptions of the intervention and to examine the preliminary efficacy in reduction of substance use and risky sex at 4-month follow-up assessment. There were consistently very high ratings of acceptability of the intervention, ranging between 6.3 and 6.8 on a 1-7 scale. At the 4-month follow-up, participants in the intervention arm reported a significantly larger reduction (54%) in any marijuana or alcohol use compared with participants in the control group (16%) (p = 0.015) based on two-group clustered logistic regression using a generalized estimating equations approach. There was a higher reduction in condomless vaginal sex at follow-up in the health checkup for expectant moms (HCEM) arm than control (27% vs. 5%), although this was not significant (p = 0.127). The results of this pilot study are encouraging with respect to the acceptability and preliminary efficacy of an intervention in reducing alcohol/marijuana use and condomless sex during pregnancy, supporting the next step of testing the intervention in a larger sample.


Nile red: Alternative to physical developer for the detection of latent fingermarks on wet porous surfaces?
This paper describes the application of a luminescent lipid stain, nile red, for the development of latent fingermarks on porous surfaces. An optimised formulation is presented that provides rapid development of latent fingermarks on porous surfaces that are or have been wet. A comparison with physical developer (PD), the method of choice to enhance such fingermarks, indicated that nile red was a simpler and more stable technique for the development of fingermarks. The nile red formulation showed similar performance to PD across a range of substrates and ageing conditions, although PD still showed greater sensitivity on five-year-old examination booklets used in a pseudo-operational study. The pseudo-operational trial also indicated that nile red consistently developed different fingermarks to those enhanced by PD, suggesting that it preferentially targets a different fraction of the latent fingermark deposit. Significantly, the compatibility of nile red in a detection sequence with indanedione-zinc, ninhydrin and PD is reported.


Insulin resistance in adolescents.
To investigate the relationship of other body mass index (BMI) ranges with Homeostasis Model Assessment-Insulin Resistance (HOMA-IR), a surrogate marker for insulin resistance in adolescents. Cross-sectional analysis of a nationally representative sample of 1837 nondiabetic, nonpregnant 12 to 19 year old persons from the National Health and Nutrition Examination Survey, 1999-2002. The main outcome measurement of insulin resistance was calculated as HOMA-IR > 3.16. Having a BMI > or = 75th percentile is associated with a high HOMA-IR levels. As the BMI percentile increases, the odds of high HOMA-IR levels increase (BMI percentile 75-84.9, OR 4.277, 95% CI 2.090-8.752; BMI percentile 85-94.9, OR 4.299, 95% CI 2.158-8.563; BMI > or = 95th percentile, OR 17.907, 95% CI 11.360-28.228). Adolescents with BMI percentile of 75 to 84.9, which represents approximately 1.2 million US adolescents, have not previously been identified as having higher HOMA-IR levels.


Growth, body composition and bone mineral density among pubertal male athletes: intra-individual 12-month changes and comparisons between soccer players and swimmers.
Puberty is a period of intense changes in human body and, additionally, participation in sports is viewed as prominent form of physical activity among male adolescent athletes. The current study was aimed to examine the intra-individual changes in body composition and bone tissue during years of maximal growth and the effect of 12-month participation in sports contrasting in mechanical impact. The sample included 40 male adolescent athletes (soccer: n = 20; swimming: n = 20) aged 12.57 ± 0.37 years who were followed for 12 months. Stature and body mass were measured, bone mineral content (BMC), areal bone mineral density (aBMD), lean soft and fat tissues assessed using DXA. Food intake was estimated using a questionnaires and training sessions individually monitored. Repeated measures ANOVA tested the differences between sports and 12-month intra-individual variation (time moments: TM1, TM2). The analyses on aBMD for total body and total body less head were repeated controlling for variation in stature at baseline. Soccer players completed 63 ± 31 sessions (95 ± 47 h). Respective values for swimmers were 248 ± 28 sessions and 390 ± 56 h. In general, the analysis of aBMD as dependent variable evidenced significant effect of sport-associated variation (F = 5.254, p < 0.01; η2 = 0.35) and 12-month increments, particularly at lower limbs (F = 97.238, p < 0.01; η2 = 0.85). Respective mean values for aBMD were SCCTM1 = 0.885 g.cm-2, SWMTM1 = 0.847 g.cm-2, SCCTM2 = 0.939 g.cm-2, SWMTM2 = 0.880. Regarding the lean soft tissue, the magnitude of effects was very large for intra-individual variation (F = 223.043, p < 0.01; η2 = 0.92) and moderate between sports (F = 7.850, p < 0.01; η2 = 0.41): SCCTM1 = 30.6 kg, SWMTM1 = 34.9 kg, SCCTM2 = 35.8 kg, SWMTM2 = 40.5 kg). Finally, d-cohen values reporting percentage of intra-individual changes in aBMD between soccer players ad swimmers were large for the trochanter (d = 1.2; annual increments: SCC = 8.1%, SWM = 3.6%). Puberty appeared as a period of significant intra-individual changes in lean soft tissue and bone mineral density. With increasing accumulated training experience, mean difference between sports contrasting in mechanical impact tended to me more pronounced in particular at the lower limbs.


Tube length of chironomid larvae as an indicator for dissolved oxygen in water bodies.
Tube-building larvae of non-biting midges, or chironomids, are considered bioindicators of water pollution. The larvae use benthic particles to make their tubes and create a respiratory current with the movement of their bodies inside the tubes. The tube length of the chironomid larvae varies depending on several physicochemical properties of the aquatic medium. Here we study the role of physicochemical parameters on the tube length from different field sites and in the laboratory. It appears that among different physicochemical factors, dissolved oxygen (DO) has a major role in determining the tube length of the larvae. A quantitative relationship between oxygen concentration and the tube length of larvae is presented here. Our study reveals a longer tube in aquatic media with oxygen deficiency and a shorter tube in those with higher oxygen. This result may help to assess the quality of water bodies and, in particular the status of DO.


[THE HIDDEN VESTIBULAR FEATURES OF MACHADO JOSEPH DISEASE (SPINOCEREBELLAR ATAXIA 3)].
Machado-Joseph disease (MJD) is an inherited neurodegenerative disease with progressive cerebellar ataxia manifested through lack of coordination and balance. MJD patients also present significant Vestibulo-Ocular Reflex (VOR) deficit but their whole vestibular features have not been previously evaluated. We aimed to evaluate whether MJD patients have vestibular features fitting the diagnostic criteria of Bilateral Vestibulopathy established by the International Society for Neuro-otology. Sixteen MJD patients and 21 healthy controls underwent a detailed clinical neuro-otological examination including a quantitative evaluation of the VOR gain using the video Head Impulse Test (vHIT). Vestibular-related symptoms were evaluated by the Dizziness Handicap Inventory (DHI), the Activities-specific Balance Confidence Scale (ABC), the Vertigo Visual Scale (VVS). In addition, anxiety that is frequently present in vestibular disorders, was evaluated by the Beck Anxiety Inventory (BAI). MJD patients had significantly reduced horizontal VOR gain with significantly higher scores in all vestibular-related symptoms questionnaires. These symptoms scores were like those reported in studies evaluating patients with bilateral peripheral vestibular loss. Beyond the cerebellar deficits, MJD patients have vestibular signs and symptoms fitting the diagnostic criteria of Bilateral Vestibulopathy established by the International Society for Neuro-otology. These findings are of relevance not only for the diagnosis and evaluation of progressive cerebellar diseases but also for the possible beneficial effect of vestibular rehabilitation techniques on dizziness, balance and the emotional, physiological and functional aspects of MJD.


Hebrew version of the physical therapy patient satisfaction questionnaire: cross-cultural adaptation and psychometric properties.
This study aimed at translating, culturally adjusting, and validating the Israeli version of the Physical Therapy Patient Satisfaction Questionnaire (PTPSQ-H). Following the process of cross-cultural adaptation of self-report measures guidelines, we conducted a cross-cultural adaptation study among of adults completing outpatient physical therapy treatments. We formulated the PTPSQ-H using forward-backward translation procedures, a final review, and a pre-final version. The applied analyses were acceptability, reliability (measured by internal consistency; Cronbach's α), and factor analysis (exploring internal structure). Divergent validity was assessed by paralleling the PTPSQ-H with pain visual analogue scale (VAS), and a 5-point Likert scale evaluating the global perceived effect (GPE) of the physical therapy treatment. Preliminary analyses concluded that five items from the PTPSQ-H are irrelevant for the study population, thus these items were removed and the questionnaire was termed the PTPSQ-H[15]. The PTPSQ-H[15] exhibited high internal consistency (α = 0.883). Divergent validity was low for the GPE (r = 0.257, p < .0001) and insignificant for the VAS (r = -0.05, p = .480). A factor analysis indicated a significant two-factor structure related to "Overall Experience" and "Professional Impression", which explained nearly 60% of the total variance assuring its suitability to measure patient satisfaction. PTPSQ-H[15] was found to be a valid tool to measure physical therapy patient satisfaction.


Issues in the management of percutaneous central venous catheters. Single and multiple lumens.
In this era of high technology and extensive parenteral therapies, multiple-lumen CVCs seem to be among the many devices needed to provide appropriate care to hospitalized patients. All CVCs, regardless of their benefit, create substantial risks for mechanical and septic complications. Antibacterial solutions that are bonded to the catheter and longer-acting skin antiseptics offer preliminary evidence that CVC sepsis rates can be reduced. The advances in CVC design, materials, and coatings are intended to be a supplement to--not a substitute for--meticulous care of CVCs.


Relative impact of CD4+CD25+ regulatory T cells and tacrolimus on inhibition of T-cell proliferation in patients with atopic dermatitis.
It has been established recently that CD4+CD25+ regulatory T cells (Tregs) play an important role in controlling various immune responses. Immunosuppressive drugs are often used to treat immune dysregulation but are frequently associated with undesirable side-effects. We examined the suppressive capacity of circulating Tregs in patients with atopic dermatitis (AD). Combined effects of Tregs and tacrolimus on the inhibition of T-cell proliferation in vitro were also assessed. CD4+CD25+ and CD4+CD25- T cells were isolated from peripheral blood mononuclear cells using immunomagnetic beads. CD4+CD25- T cells were stimulated with purified protein derivative (PPD) or house dust mite allergen (Der p1) for 6 or 7 days, respectively. A dose range of tacrolimus and CD4+CD25+ T cells were added separately, or together. Proliferation was measured by (3)H-thymidine incorporation. CD4+CD25+ T cells from normal controls and patients with AD are anergic and inhibit the proliferation of CD4+CD25- T cells in response to PPD and Der p1 in vitro in a dose-dependent manner. Addition of tacrolimus and Tregs together showed significantly stronger inhibition of proliferation than either on their own. This was true for both antigens and both in normal controls and in patients with AD. CD4+CD25+ T cells in patients with AD have normal suppressive activity compared with healthy controls. Tregs and tacrolimus have additive effects on the inhibition of proliferation in response to PPD and Der p1.


A comparison of a T1 weighted 3D gradient-echo sequence with three different parallel imaging reduction factors, breath hold and free breathing, using a 32 channel coil at 1.5 T. A preliminary study.
To investigate whether increasing temporal resolution with higher parallel imaging (PI) reduction factors (RF) in both breath-hold and free breathing approaches, using a non-contrast T1-weighted 3D gradient echo (GRE) sequence and a 32-channel phased array coil, permits diagnostic image quality, with potential application in patients unable to cooperate with breath-hold requirements. The 9 healthy subjects (5 females and 4 males; age range was 20-49, mean 36 yrs) were recruited. A 3D GRE MR imaging of the abdomen was performed on 1.5 T MR system using a 32-element phased-array torso coil with PI RFs of 2, 4 and 6, breath hold and free breathing. Two reviewers retrospectively qualitatively evaluated all sequences for image quality, extent of artifacts, including motion, truncation, aliasing, pixel graininess and signal heterogeneity. The results were compared using Wilcoxon signed rank and a Bonferroni adjustment was applied for multiple comparisons. Image quality and extent of artifacts were better with breath hold than with free breathing acquisitions. The rate of artifacts increased with higher RF. The best quality was acquired with breath hold sequence using RF=2. RF=4 had lower but diagnostic rates (P=.004). The severity of artifacts, mainly pixel graininess (P=.004), rendered sequences with RF=6 non-diagnostic. All sequences were non-diagnostic in free breathing acquisitions. Breath hold sequences with RF=2 had excellent quality and RF=4 had good quality and may be potentially used in partially cooperative patients. None of the sequences was considered diagnostic in free breathing acquisitions.


Immune function keeps endosymbionts under control.
How does an animal host prevent intracellular symbionts getting out of hand? A new paper in BMC Biology provides evidence that the mutualism between a beetle and its bacterial endosymbiont could be mediated through the expression of host immune genes.


Evolution of a refractory prolactin-secreting pituitary adenoma into a pituitary carcinoma: report of a challenging case and literature review.
Pituitary carcinomas (PCs), defined as distant metastases of pituitary neoplasms, are very rare malignancies. Because the clinical presentation of PCs is variable, early diagnosis and management remain challenging. PCs are always refractory to comprehensive treatments, and patients with PCs have extremely poor prognoses. We describe one case of a prolactin-secreting pituitary adenoma (PA) refractory to conventional therapy that evolved into a PC with intraspinal metastasis. A 34-year-old female was diagnosed with an invasive prolactin-secreting PA in 2009 and was unresponsive to medical treatment with bromocriptine. The tumor was gross totally removed via transsphenoidal surgery (TSS). However, the patient experienced multiple tumor recurrences or regrowth despite comprehensive treatments, including medical therapy, two gamma knife radiosurgeries (GKSs), and four frontal craniotomies. In 2016, she was found to have an intradural extramedullary mass at the level of the fourth lumbar vertebra. The intraspinal lesion was completely resected and was confirmed as a metastatic PC based on histomorphology and immunohistochemical staining. The literature on the diagnosis, molecular pathogenesis, treatment, and prognosis of patients with prolactin-secreting PCs was reviewed. PCs are very rare neoplasms with variable clinical features and poor prognosis. Most PCs usually arise from aggressive PAs refractory to conventional therapy. There is no reliable marker to identify aggressive PAs with a risk for progression to PCs; thus, it is difficult to diagnose these PCs early until the presence of metastatic lesions. It is still very challenging to manage patients with PCs due to a lack of standardized protocols for diagnosis and treatment. Establishing molecular biomarkers and the pathobiology of PCs could help in the early identification of aggressive PAs most likely to evolve into PCs.


Inhibition of enkephalin metabolism and activation of mu- or delta-opioid receptors elicit opposite effects on reward and motility in the ventral mesencephalon.
The coexistence of endogenous opioid systems and dopaminergic neurones in the midbrain tegmental area suggests functional interactions between dopamine and enkephalins. Nevertheless, the identification of the specific opioid receptors associated with modulation of tegmental dopamine activity and its behavioural concomitants on motility and reward is far from clear, considering the mixed nature of the ligands usually employed. In this way, kelatorphan, a potent inhibitor of enkephalinases and selective agonists for mu- and delta-opioid receptor subtypes (DAGO and DSTBULET, respectively) were infused directly into the ventral tegmental area of the rat to study the role of endogenous enkephalins and opioid receptors in regulating spontaneous motor activity and intracranial self-stimulation behaviour. A greater increase in the rate of intracranial self-stimulation behaviour was found after activation of mu-opioid receptors in the ventral tegmental area, as compared to activation of delta-opioid receptors, whereas enhancement of endogenous enkephalins by inhibiting their metabolism through kelatorphan, reduced the rate of intracranial self-stimulation behaviour. On the contrary, spontaneous motor activity was reduced by the delta-opioid receptor agonist, whereas kelatorphan increased the movements of the animal. Taken together, these results show that inhibition of the metabolism of enkephalins in the ventral tegmental area decreased positive reinforcement from the lateral hypothalamic medial forebrain bundle and increased spontaneous movements. On the contrary, activation of both mu- or delta-opioid receptors in the ventral tegmental area significantly increased self-stimulation and decreased spontaneous motor activity, supporting the view that different mechanisms underlie the behavioural effects, resulting from enhancement of endogenous enkephalins and from activation of specific opioid receptors in the ventral mesencephalon.


ATAC is a double histone acetyltransferase complex that stimulates nucleosome sliding.
The Ada2a-containing (ATAC) complex is an essential Drosophila melanogaster histone acetyltransferase (HAT) complex that contains the transcriptional cofactors Gcn5 (KAT2), Ada3, Ada2a, Atac1 and Hcf. We have analyzed the complex by MudPIT (multidimensional protein identification technology) and found eight previously unidentified subunits. These include the WD40 repeat protein WDS, the PHD and HAT domain protein CG10414 (herein renamed Atac2/KAT14), the YEATS family member D12, the histone fold proteins CHRAC14 and NC2beta, CG30390, CG32343 (Atac3) and CG10238. The presence of CG10414 (Atac2) suggests that it acts as a second acetyltransferase enzyme in ATAC in addition to Gcn5. Indeed, recombinant Atac2 displays HAT activity in vitro with a preference for acetylating histone H4, and mutation of Atac2 abrogated H4 lysine 16 acetylation in D. melanogaster embryos. Furthermore, although ATAC does not show nucleosome-remodeling activity itself, it stimulates nucleosome sliding by the ISWI, SWI-SNF and RSC complexes.


[The risk of cerebrovascular complications in the combination of pregnancy and mitral valve prolapse].
A case of left intraventricular thrombus, developed from a myxoid mitral valve and revealed by embolic cerebral vascular accidents at the end of a pregnancy, is reported. The links between a mitral valve prolapse and cerebral vascular accidents of embolic origin are studied during pre- and post-partum periods, where coagulation alterations are reviewed. It appears that, in pregnant women with a mitral valve prolapse, there is a maximum risk of developing an intra-cardiac thrombus in the last four weeks of pregnancy or immediately after delivery; this justifies, during that time, a thorough sonocardiographic monitoring.


Long-term effects of intraoperative topical bevacizumab in sutureless scleral tunnel trabeculectomy: a prospective clinical trial.
To investigate the long-term efficacy and safety of the novel method sutureless trabeculectomy with topical administration of bevacizumab. Primary open-angle glaucoma patients with intraocular pressure (IOP) > 21 mmHg despite maximum tolerated medication were included in a single-blind prospective interventional clinical trial. Group 1 underwent sutureless scleral tunnel trabeculectomy with intraoperative topical administration of bevacizumab (1.25 mg) applied on the scleral incision for 1 min. Group 2 underwent sutureless trabeculectomy alone and group 3 (control group) underwent conventional trabeculectomy with mitomycin C (MMC). Outcome measures were surgical success, IOP, number of needed anti-glaucoma medications, and complications. Patients were followed for two years. Finally, 50 eyes from group 1, 46 from group 2, and 47 from group 3 were analyzed. At the end of 24 months, 52% (n = 26) of group 1, 34.8% (n = 16) of group 2, and 57.4% (n = 27) of group 3 had complete success (IOP < 18 mmHg without medication). The difference was only significant between groups 2 and 3 (p = 0.003). 94% (n = 47) of group 1, 89.1% (n = 41) of group 2, and 91.5% (n = 43) of group 3 had qualified success (IOP < 18 mmHg with ≤ 2 anti-glaucoma medications) (p = 0.69). There was a significant difference in the overall IOP mean between the three groups (p < 0.0001). There was no significant difference between the three groups in complication rates and the number of needed anti-glaucoma medications for IOP control. Sutureless trabeculectomy with topical application of bevacizumab showed comparable surgical success rates with conventional trabeculectomy and MMC in long-term follow-up. Additionally, adjuvant use of topical bevacizumab had a significant positive impact on long-term IOP control.


The Utility of Exercise Testing in Risk Stratification of Asymptomatic Patients With Type 1 Brugada Pattern.
Risk stratification of asymptomatic patients with a Brugada type 1 ECG pattern remains an unresolved clinical conundrum. In contrast to provocative pharmacological testing in Brugada syndrome, there is limited data on the role of exercise stress testing as a risk stratification modality. The objective of this study was to evaluate the utility of exercise testing in asymptomatic patients with type 1 Brugada pattern to prognosticate major arrhythmic events (MAE) during follow-up. Treadmill exercise testing was conducted for 75 asymptomatic patients with type 1 Brugada pattern and for 88 healthy control subjects. The clinical end point of MAE was defined as the occurrence of sudden cardiac death (SCD) or resuscitated ventricular fibrillation (VF). During a follow-up of 77.9 ± 28.9 months, eight MAE occurred (five VF and three SCD). Multivariate Cox regression analysis showed that the following were independent predictors of MAE in asymptomatic patients with a type 1 Brugada pattern: increase in S wave upslope duration ratio >30% at peak exercise (HR 1.35, 95% CI 1.08-10.97, P = 0.023), augmentation of J point elevation in lead aVR >2 mm in late recovery (HR 1.88, 95% 1.21-15.67, P = 0.011), and delayed HR recovery (HR 1.14, 95% CI 1.06-18.22, P = 0.042). A high-risk cohort was identified by the final step-wise regression model with good accuracy (specificity = 98.4%, sensitivity = 62.5%) and discriminative power (AUC = 0.93, 95% CI 0.89-0.96, P = 0.002). Kaplan-Meier analysis revealed increasing MAE in subjects with one, two, or three predictors, respectively (log rank P < 0.001). Exercise testing in asymptomatic patients with type 1 Brugada pattern aids in identification of high-risk patients and provides a unique window of opportunity for early intervention.


Paravertebral mediastinal Mullerian cyst resected by video assisted thoracoscopic surgery.
Ever since Hattori et al. had described the mediastinal Mullerian cyst in 2005 there has been several new cases described in the literature. We report a 51-year-old woman with an incidentally found 2 cm × 3 cm mass in her left paravertebral mediastinum. She underwent thoracoscopic removal with the impression of a neurogenic tumor and was unexpectedly found with a ciliated cyst of Mullerian origin.


Morphological changes of labyrinthine blood vessels following metal poisoning.
Metal intoxication (mercury and arsenic) in guinea pigs may cause damage to labyrinthine blood vessels by swelling of the endothelial cells, mitochondrial disintegration and sometimes protrusion of endothelial cell cytoplasm herniating into the blood vessel lumen. Chronic mercury intoxication resulted in distorted endothelial cells with an increase in the density of their cytoplasm. An altered vascular permeability is likely to occur as the result of the morphological changes.


[Diastematomyelia--a harmless finding or cause of late neurological disturbance? (author's transl)].
Diastematomyelia is said to produce neurological lesions. Several new cases of diastematomyelia are reported without any neurological defect. They are discussed and compared with similar cases from the literature. Apparently the fixation of the spinal cord by diastematomyelia seems not to be the primary cause of the "tethering cord syndrome". Other conditions which are sometimes associated with diastematomyelia (myelodysplasia, dysraphia of the spinal cord etc.) may be the primary cause of progressive neurological lesions.


Health needs of older adults displaced to Sudan by war and famine: questioning current targeting practices in health relief.
The high rates of death, disability and illness and the scarcity of resources associated with relief operations for victims of oppression, war and famine have led to some support systems of triage for health and nutritional care in relief. Two vulnerable groups have often been given priority for targeting in health relief--young children and their mothers. This paper reports the findings of a study of the health needs of another vulnerable group, older adults, among those who had been recently displaced to Sudan in 1984-1985 by the war and famine in Tigray region of Ethiopia. The study attempted to determine the extent to which morbidity events and migration affected the life-style of older adults and the socio-economic support mechanisms which were available to them. The findings indicate that older adults (those over 45 years of age) were a very small proportion of the population and that over half of those aged 60 years and over (defined as 'elderly' in this paper) had been left behind in Tigray. This may well indicate that disability, illness or both, forced many older adults, particularly those most in need, to remain in Tigray. Among older adults living in Sudan, high levels of minor disability, social isolation and total economic dependency indicated vulnerability, but older adults had not been specifically considered in health policies and plans. Their primary needs were basic--for cloth, food, shelter, transport, seeds, oxen and farming tools. We conclude that priority in relief should be to support individuals, families and entire communities by adequately providing for basic needs. Furthermore, international relief agencies should give equal consideration to those who remain in their homes and those who migrate for assistance. This approach would take into consideration quality of life, not just the number of lives saved among those who reach the camps and shelters, and would assume responsibility for 'Health for All', not just for selected 'vulnerable groups'.


Lymphokine-release from rainbow trout leucocytes stimulated with concanavalin A. Effects upon macrophage spreading and adherence.
Rainbow trout blood and head kidney leucocytes were stimulated with the mitogen ConA to release a factor(s) that increased macrophage spreading and adherence. ConA present in control cultures was also shown to have this effect and so removal of ConA was essential to investigate the action of potential lymphokines. Either a 3h pulse with ConA or absorption of supernatants with Sephadex G10 was found to successfully remove activity from control supernatants whilst having no effect upon the lymphokine-containing supernatants.


Repair versus Debridement for Acetabular Labral Tears-A Systematic Review.
The purpose of this study was to systematically review the evidence in the literature to ascertain whether acetabular labral repair (ALR) or debridement (ALD) resulted in superior patient outcomes. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Peer-reviewed studies comparing ALR and ALD published in English with full text available were included. Patients undergoing both open and arthroscopic surgery in randomized controlled trials, prospective cohort studies, retrospective cohort studies, and case-control studies were included. Studies were quantified for methodological quality using the MINORS criteria. Clinical outcomes were compared, with qualitative analysis, and quantitative analyses were performed using GraphPad Prism version 7. A P value <.05 was considered to be statistically significant. There were 8 studies included (level of evidence [LOE] I = 1; LOE II = 2; LOE III = 5). The 7 studies compared 364 patients (369 hips) with ALR to 318 patients (329 hips) with ALD, with a mean follow-up time ranging between 32-120 months. Five studies found significantly improved patient reported outcomes with ALR (Harris Hip Score, Merle d'Aubigné, Pain, SF-12). Several studies compared the outcomes after ALR and ALD and found statistical significance in all investigated metrics in favor of ALR. One study found a significant improvement in abduction but no other study found any difference in range of motion. No study found any difference in complication rate, revision rate or conversion to total hip arthroplasty. Although, 2 studies found ALR reduced the rate of osteoarthritic progression. Current literature suggests that acetabular labral repair may result in superior patient reported outcomes. However, there appears to be no significant difference in the rate of progression to total hip arthroplasty at up to 10-year follow-up. Level III, systematic review of Level I, II, and III studies.


Panel discussion: glomus jugulare tumors of the temporal bone. Patterns of invasion in the temporal bone.
The purpose of this paper is to enumerate and define the exact patterns of glomus jugulare tumor invasion in the temporal bone. Special attention will be focused on those pathways which lead to central nervous system (CNS) invasion.


Molecular complex detection in protein interaction networks through reinforcement learning.
Proteins often assemble into higher-order complexes to perform their biological functions. Such protein-protein interactions (PPI) are often experimentally measured for pairs of proteins and summarized in a weighted PPI network, to which community detection algorithms can be applied to define the various higher-order protein complexes. Current methods include unsupervised and supervised approaches, often assuming that protein complexes manifest only as dense subgraphs. Utilizing supervised approaches, the focus is not on how to find them in a network, but only on learning which subgraphs correspond to complexes, currently solved using heuristics. However, learning to walk trajectories on a network to identify protein complexes leads naturally to a reinforcement learning (RL) approach, a strategy not extensively explored for community detection. Here, we develop and evaluate a reinforcement learning pipeline for community detection on weighted protein-protein interaction networks to detect new protein complexes. The algorithm is trained to calculate the value of different subgraphs encountered while walking on the network to reconstruct known complexes. A distributed prediction algorithm then scales the RL pipeline to search for novel protein complexes on large PPI networks. The reinforcement learning pipeline is applied to a human PPI network consisting of 8k proteins and 60k PPI, which results in 1,157 protein complexes. The method demonstrated competitive accuracy with improved speed compared to previous algorithms. We highlight protein complexes such as C4orf19, C18orf21, and KIAA1522 which are currently minimally characterized. Additionally, the results suggest TMC04 be a putative additional subunit of the KICSTOR complex and confirm the involvement of C15orf41 in a higher-order complex with HIRA, CDAN1, ASF1A, and by 3D structural modeling. Reinforcement learning offers several distinct advantages for community detection, including scalability and knowledge of the walk trajectories defining those communities. Applied to currently available human protein interaction networks, this method had comparable accuracy with other algorithms and notable savings in computational time, and in turn, led to clear predictions of protein function and interactions for several uncharacterized human proteins.


Tuning the ignition of CAR: optimizing the affinity of scFv to improve CAR-T therapy.
How single-chain variable fragments (scFvs) affect the functions of chimeric antigen receptors (CARs) has not been well studied. Here, the components of CAR with an emphasis on scFv were described, and then several methods to measure scFv affinity were discussed. Next, scFv optimization studies for CD19, CD38, HER2, GD2 or EGFR were overviewed, showing that tuning the affinity of scFv could alleviate the on-target/off-tumor toxicity. The affinities of scFvs for different antigens were also summarized to designate a relatively optimal working range for CAR design. Last, a synthetic biology approach utilizing a low-affinity synthetic Notch (synNotch) receptor to achieve ultrasensitivity of antigen-density discrimination and murine models to assay the on-target/off-tumor toxicity of CARs were highlighted. Thus, this review provides preliminary guidelines of choosing the right scFvs for CARs.


Nutritional outcomes in patients undergoing transoral robotic surgery for head and neck cancers compared to conventional open surgery. Systematic review.
This systematic review examined nutritional outcomes in patients undergoing transoral robotic surgery (TORS), compared to open surgery (OS) for head and neck cancer. PUBMED, CINAHL, and Web of Science were systematically reviewed. Target nutritional outcomes included: weight, nutritional status, use of enteral feeding, swallowing function/ability, and time to oral diet. Risk of bias was assessed using the risk of bias in non-randomized studies tool, and certainty of evidence was assessed using grading of recommendations, assessment, development, and evaluation (GRADE). Eight studies were included (total n = 608). Compared to OS, TORS probably reduces short- and long-term enteral feeding use or duration (GRADE "moderate" certainty), may reduce time to full swallow ability (GRADE "low" certainty), but it remains uncertain whether TORS reduces long-term patient reported swallowing function or time to oral feeding (GRADE "very-low" certainty). No studies examined nutritional status or weight. There is limited body of evidence examining nutrition outcomes following TORS. Further studies are warranted, which may improve the certainty of evidence and assist in determining the optimal nutrition care for these patients.