Hydraulic redistribution in three Amazonian trees.
About half of the Amazon rainforest is subject to seasonal droughts of 3 months or more. Despite this drought, several studies have shown that these forests, under a strongly seasonal climate, do not exhibit significant water stress during the dry season. In addition to deep soil water uptake, another contributing explanation for the absence of plant water stress during drought is the process of hydraulic redistribution; the nocturnal transfer of water by roots from moist to dry regions of the soil profile. Here, we present data on patterns of soil moisture and sap flow in roots of three dimorphic-rooted species in the Tapajós Forest, Amazônia, which demonstrate both upward (hydraulic lift) and downward hydraulic redistribution. We measured sap flow in lateral and tap roots of our three study species over a 2-year period using the heat ratio method, a sap-flow technique that allows bi-directional measurement of water flow. On certain nights during the dry season, reverse or acropetal flow (i.e.,in the direction of the soil) in the lateral roots and positive or basipetal sap flow (toward the plant) in the tap roots of Coussarea racemosa (caferana), Manilkara huberi (maçaranduba) and Protium robustum (breu) were observed, a pattern consistent with upward hydraulic redistribution (hydraulic lift). With the onset of heavy rains, this pattern reversed, with continuous night-time acropetal sap flow in the tap root and basipetal sap flow in lateral roots, indicating water movement from wet top soil to dry deeper soils (downward hydraulic redistribution). Both patterns were present in trees within a rainfall exclusion plot (Seca Floresta) and to a more limited extent in the control plot. Although hydraulic redistribution has traditionally been associated with arid or strongly seasonal environments, our findings now suggest that it is important in ameliorating water stress and improving rain infiltration in Amazonian rainforests. This has broad implications for understanding and modeling ecosystem process and forest function in this important biome.


Detection of phenotype modifier genes using two-locus linkage analysis in complex disorders such as major psychosis.
To increase power to detect modifier loci conferring susceptibility to specific phenotypes such as disease diagnoses which are part of a broader disorder spectrum by jointly modeling a modifier and a broad susceptibility gene and to identify modifier loci conferring specific susceptibility to schizophrenia (SZ) or to bipolar disorder (BP) using the approach. We implemented a two-locus linkage analysis model where a gene 1 genotype increases the risk of a broad phenotype and a gene 2 genotype modifies the expression of gene 1 by conferring susceptibility to a specific phenotype. Compared to a single-locus analysis within the broad phenotype, the proposed approach had greater power to detect the modifier gene 2 (0.96 vs. 0.54 under a simulation scenario including heterogeneity). In a sample of 12 mixed SZ and BP Eastern Quebec kindreds, D8S1110 at 8p22 showed the strongest evidence of linkage to a gene determining a specific phenotype (SZ or BP) among subjects susceptible to major psychosis because of putative genes at 10p13 (D10S245, conditional maximized LOD (cMOD) = 4.20, p = 0.0003) and 3q21-q23 (D3S2418, cMOD = 4.09, p = 0.0005). The proposed strategy is useful to detect modifier loci conferring susceptibility to a specific phenotype within a broader phenotype.


(+)-Pentazocine Reduces NMDA-Induced Murine Retinal Ganglion Cell Death Through a σR1-Dependent Mechanism.
To evaluate, in vivo, the effects of the sigma-1 receptor (σR1) agonist, (+)-pentazocine, on N-methyl-D-aspartate (NMDA)-mediated retinal excitotoxicity. Intravitreal NMDA injections were performed in C57BL/6J mice (wild type [WT]) and σR1-/- (σR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and σR1 KO mice was administered (+)-pentazocine by intraperitoneal injection, and untreated animals served as controls. Retinas derived from mice were flat-mounted and labeled for retinal ganglion cells (RGCs). The number of RGCs was compared between NMDA and PBS-injected eyes for all groups. Apoptosis was assessed using TUNEL assay. Levels of extracellular-signal-regulated kinases (ERK1/2) were analyzed by Western blot. N-methyl-D-aspartate induced a significant increase in TUNEL-positive nuclei and a dose-dependent loss of RGCs. Mice deficient in σR1 showed greater RGC loss (≈80%) than WT animals (≈50%). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of σR1. (+)-Pentazocine treatment resulted in enhanced activation of ERK at the 6-hour time point following NMDA injection. The (+)-pentazocine-induced ERK activation was diminished in σR1 KO mice. Targeting σR1 activation prevented RGC death while enhancing activation of the mitogen-activated protein kinase (MAPK), ERK1/2. Sigma-1 receptor is a promising therapeutic target for retinal neurodegenerative diseases.


Quantitative iTRAQ secretome analysis of Aspergillus niger reveals novel hydrolytic enzymes.
The natural lifestyle of Aspergillus niger made them more effective secretors of hydrolytic proteins and becomes critical when this species were exploited as hosts for the commercial secretion of heterologous proteins. The protein secretion profile of A. niger and its mutant at different pH was explored using iTRAQ-based quantitative proteomics approach coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). This study characterized 102 highly confident unique proteins in the secretome with zero false discovery rate based on decoy strategy. The iTRAQ technique identified and relatively quantified many hydrolyzing enzymes such as cellulases, hemicellulases, glycoside hydrolases, proteases, peroxidases, and protein translocating transporter proteins during fermentation. The enzymes have potential application in lignocellulosic biomass hydrolysis for biofuel production, for example, the cellulolytic and hemicellulolytic enzymes glucan 1,4-alpha-glucosidase, alpha-glucosidase C, endoglucanase, alpha l-arabinofuranosidase, beta-mannosidase, glycosyl hydrolase; proteases such as tripeptidyl-peptidase, aspergillopepsin, and other enzymes including cytochrome c oxidase, cytochrome c oxidase, glucose oxidase were highly expressed in A. niger and its mutant secretion. In addition, specific enzyme production can be stimulated by controlling pH of the culture medium. Our results showed comprehensive unique secretory protein profile of A. niger, its regulation at different pH, and the potential application of iTRAQ-based quantitative proteomics for the microbial secretome analysis.


Operator constitutive mutation of 3-hydroxy-3-methylglutaryl coenzyme A reductase promoter abolishes protein binding to sterol regulatory element.
Through substitution mutagenesis we identified the promoter elements responsible for basal expression and sterol-mediated repression of transcription of the gene for 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-controlling enzyme of cholesterol biosynthesis. Mutant promoters containing 277 base pairs (bp) of reductase 5' flanking sequence were inserted into recombinant plasmids upstream of the coding region for bacterial chloramphenicol acetyltransferase. The plasmids were transfected into hamster fibroblasts, and transcription was measured in the presence and absence of sterols. Mutations in three regions that are known to bind nuclear proteins markedly reduced transcription. Mutation of another protein-binding region of 20 bp in length did not reduce transcription, but it did abolish sterol-mediated repression, producing an operator constitutive phenotype. This mutation also abolished protein binding to the corresponding 20-bp region of DNA as determined by footprinting assays. When a DNA fragment containing these 20 bp was inserted into the herpes simplex virus thymidine kinase promoter, sterol-mediated repression was observed. This sequence contains an octanucleotide that shows a 7/8-bp match with a previously identified regulatory sequence in repeat 2 of the low density lipoprotein receptor promoter, another sterol-repressible gene. We hypothesize that this octanucleotide, GTGGCGGTG, is the core binding site for a sterol-dependent protein that represses transcription.


Microbial forensics for natural and intentional incidents of infectious disease involving animals.
Microbial forensics is a relatively new scientific discipline dedicated to analysing microbiological evidence from a crime for attribution purposes. It builds on traditional microbiology and epidemiology but within a legal framework. Important motives for forensic investigations include interdiction of criminals, prosecution of justice, and ideally, deterrence of others from committing similar acts. Forensic capabilities in animal health should focus on building capacity for detection and reporting of increases in infectious disease morbidity and mortality among animals that might reflect a covert release of a pathogen. Suspicion should be raised when epidemiological patterns are different from those expected for the animal population and the pathogen in question. Existing capacities for the detection and reporting of epidemic and even endemic diseases should be an international priority for the prevention of catastrophic losses in animal and potentially in human life. The veterinary community needs to be more aware of the legal requirements related to forensic investigations so that veterinarians will be prepared to handle evidence properly within their own fields.


Learning how to learn using simulation: Unpacking disguised feedback using a qualitative analysis of doctors' telephone talk.
Telephone talk between clinicians represents a substantial workplace activity in postgraduate clinical education, yet junior doctors receive little training in goal-directed, professional telephone communication. To assess educational needs for telephone talk and develop a simulation-based educational intervention. Thematic analysis of 17 semi-structured interviews with doctors-in-training from various training levels and specialties. We identified essential elements to incorporate into simulation-based telephone talk, including common challenging situations for junior doctors as well as explicit and informal aspects that promote learning. These elements have implications for both junior doctors and clinical supervisors, including: (a) explicit teaching and feedback practices and (b) informal conversational interruptions and questions. The latter serve as "disguised" feedback, which aligns with recent conceptualizations of feedback as "performance relevant information". In addition to preparing clinical supervisors to support learning through telephone talk, we propose several potential educational strategies: (a) embedding telephone communication skills throughout simulation activities and (b) developing stand-alone curricular elements to sensitize junior doctors to "disguised" feedback during telephone talk as a mechanism to augment future workplace learning, i.e. 'learning how to learn' through simulation.


Randomised controlled trial of integrated care to reduce disability from chronic low back pain in working and private life.
To evaluate the effectiveness of an integrated care programme, combining a patient directed and a workplace directed intervention, for patients with chronic low back pain. Population based randomised controlled trial. Primary care (10 physiotherapy practices, one occupational health service, one occupational therapy practice) and secondary care (five hospitals). 134 adults aged 18-65 sick listed for at least 12 weeks owing to low back pain. Patients were randomly assigned to usual care (n=68) or integrated care (n=66). Integrated care consisted of a workplace intervention based on participatory ergonomics, involving a supervisor, and a graded activity programme based on cognitive behavioural principles. The primary outcome was the duration of time off work (work disability) due to low back pain until full sustainable return to work. Secondary outcome measures were intensity of pain and functional status. The median duration until sustainable return to work was 88 days in the integrated care group compared with 208 days in the usual care group (P=0.003). Integrated care was effective on return to work (hazard ratio 1.9, 95% confidence interval 1.2 to 2.8, P=0.004). After 12 months, patients in the integrated care group improved significantly more on functional status compared with patients in the usual care group (P=0.01). Improvement of pain between the groups did not differ significantly. The integrated care programme substantially reduced disability due to chronic low back pain in private and working life. Trial registration Current Controlled Trials ISRCTN28478651.


Comparison of High-Hydrostatic-Pressure Decellularized Versus Freeze-Thawed Porcine Menisci.
The meniscus functions as a load distributor and secondary stabilizer in the knee, and the loss of the meniscus increases the risk of osteoarthritis. Freeze-thawed menisci are used in clinical practice to replace defective menisci; however, the disadvantages of freeze-thawed tissues include disease transmission and immune rejection. In this study, we decellularized menisci using high hydrostatic pressure (HHP) and compared the decellularized menisci with freeze-thawed menisci. Porcine menisci were either pressurized at 1,000 MPa for 10 min and then washed with DNase solution or frozen at -80°C for 2 days and thawed. These menisci then underwent in vitro histological, biochemical, and biomechanical comparisons with native menisci. The HHP-treated and freeze-thawed menisci were also subcutaneously implanted in a pig, and later harvested for histological analysis. The numbers of histologically detected cells were significantly lower and the amount of biochemically detected DNA was approximately 100-fold lower in HHP-treated than in native and freeze-thawed menisci. The compression strength of the HHP-decellularized menisci was decreased after 1 and 50 cycles at 20% strain but was unchanged in the freeze-thawed menisci. After implantation, the numbers of multinucleated giant cells were significantly lower around the HHP-treated menisci than around the freeze-thawed menisci. Recellularization of the HHP-decellularized menisci was confirmed. Thus, although the HHP-decellularized menisci were mechanically inferior to the freeze-thawed meniscus in vitro, they were immunologically superior. Our study is the first to demonstrate the use of HHP for decellularization of the meniscus. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2466-2475, 2019.


Role of megalin (gp330) in transcytosis of thyroglobulin by thyroid cells. A novel function in the control of thyroid hormone release.
When thyroglobulin (Tg) is endocytosed by thyrocytes and transported to lysosomes, thyroid hormones (T4 and T3) are released. However, some internalized Tg is transcytosed intact into the bloodstream, thereby avoiding proteolytic cleavage. Here we show that megalin (gp330), a Tg receptor on thyroid cells, plays a role in Tg transcytosis. Following incubation with exogenous rat Tg at 37 degrees C, Fisher rat thyroid (FRTL-5) cells, a differentiated thyroid cell line, released T3 into the medium. However, when cells were incubated with Tg plus either of two megalin competitors, T3 release was increased, suggesting that Tg internalized by megalin bypassed the lysosomal pathway, possibly with release of undegraded Tg from cells. To assess this possibility, we performed experiments in which FRTL-5 cells were incubated with either unlabeled or (125)I-labeled Tg at 37 degrees C to allow internalization, treated with heparin to remove cell surface-bound Tg, and further incubated at 37 degrees C to allow Tg release. Intact 330-kDa Tg was released into the medium, and the amount released was markedly reduced by megalin competitors. To investigate whether Tg release resulted from transcytosis, we studied FRTL-5 cells cultured as polarized layers with tight junctions on permeable filters in the upper chamber of dual chambered devices. Following the addition of Tg to the upper chamber and incubation at 37 degrees C, intact 330-kDa Tg was found in fluids collected from the lower chamber. The amount recovered was markedly reduced by megalin competitors, indicating that megalin mediates Tg transcytosis. We also studied Tg transcytosis in vivo, using a rat model of goiter induced by aminotriazole, in which increased release of thyrotropin induces massive colloid endocytosis. This was associated with increased megalin expression on thyrocytes and increased serum Tg levels, with reduced serum T3 levels, supporting the conclusion that megalin mediates Tg transcytosis. Tg transcytosis is a novel function of megalin, which usually transports ligands to lysosomes. Megalin-mediated transcytosis may regulate the extent of thyroid hormone release.


GlideScope versus D-blade for tracheal intubation in cervical spine patients: A randomised controlled trial.
Airway management in patients with cervical spine pathology is challenging. The aim of the study was to evaluate GlideScope (GVL) and D blade of C-MAC (CMAC-D) using manual inline axial stabilisation (MIAS) for tracheal intubation in patients with cervical spine injury/pathology. This is a randomised, single-blind, hospital-based study. After obtaining informed consent, 54 patients with cervical spine pathology/injury were grouped into GVL group or CMAC-D group, (n = 27 each) based on computer-generated random number table. Preoperative airway difficulty score (ADS) was calculated. The primary outcome of the study was intubation difficulty score (IDS) and the secondary outcomes included total time taken to secure airway, failure to intubate, haemodynamic parameters and adverse events. Data was represented in the form of number (%) or mean and standard deviation and median and interquartile range as appropriate. Chi square test was used for analysing IDS. The mean ± SD of IDS of the CMAC-D and GVL groups were 0.04 ± 0.2 (0.04-0.11) and 0.19 ± 0.40 (0.03-0.34), respectively, (P value = 0.096). The number (%) of patients with IDS > 0 was 1 (3.7) in CMAC-D and 5 (18.5) in GVL group, (P value = 0.192). Demographic data, ADS, Cormack-Lehane grading, success rate, time of tracheal intubation, type of surgeries, haemodynamic parameters and post-operative complications were similar in both the groups. Both GVL and CMAC-D with MIAS are equally efficacious in tracheal intubation in cervical spine injury/pathology patients without other difficult airway management criteria.


Enhancing cell seeding and osteogenesis of MSCs on 3D printed scaffolds through injectable BMP2 immobilized ECM-Mimetic gel.
Design of bioactive scaffolds with osteogenic capacity is a central challenge in cell-based patient-specific bone tissue engineering. Efficient and spatially uniform seeding of (stem) cells onto such constructs is vital to attain functional tissues. Herein we developed heparin functionalized collagen gels supported by 3D printed bioceramic scaffolds, as bone extracellular matrix (ECM)-mimetic matrices. These matrices were designed to enhance cell seeding efficiency of mesenchymal stem cells (MSCs) as well as improve their osteogenic differentiation through immobilized bone morphogenic protein 2 (BMP2) to be used for personalized bone regeneration. A 3D gel based on heparin-conjugated collagen matrix capable of immobilizing recombinant human bone morphogenic protein 2 (BMP2) was synthesized. Isolated dental pulp Mesenchymal stem cells (MSCs) were then encapsulated into the bone ECM microenvironment to efficiently and uniformly seed a bioactive ceramic-based scaffold fabricated using additive manufacturing technique. The designed 3D cell-laden constructs were comprehensively investigated trough in vitro assays and in vivo study. In-depth rheological characterizations of heparin-conjugated collagen gel revealed that elasticity of the matrix is significantly improved compared with freely incorporated heparin. Investigation of the MSCs laden collagen-heparin hydrogels revealed their capability to provide spatiotemporal bioavailability of BMP2 while suppressing the matrix contraction over time. The in vivo histology and real-time polymerase chain reaction (qPCR) analysis showed that the designed construct supported the osteogenic differentiation of MSCs and induced the ectopic bone formation in rat model. The presented hybrid constructs combine bone ECM chemical cues with mechanical function providing an ideal 3D microenvironment for patient-specific bone tissue engineering and cell therapy applications. The implemented methodology in design of ECM-mimetic 3D matrix capable of immobilizing BMP2 to improve seeding efficiency of customized scaffolds can be exploited for other bioactive molecules.


Education and self-management for people newly diagnosed with type 2 diabetes: a qualitative study of patients' views.
We explored the perceptions, views and experiences of diabetes education in people with type 2 diabetes who were participating in a UK randomized controlled trial of methods of education. The intervention arm of the trial was based on DESMOND, a structured programme of group education sessions aimed at enabling self-management of diabetes, while the standard arm was usual care from general practices. Individual semi-structured interviews were conducted with 36 adult patients, of whom 19 had attended DESMOND education sessions and 17 had been randomized to receive usual care. Data analysis was based on the constant comparative method. Four principal orientations towards diabetes and its management were identified: 'resisters', 'identity resisters, consequence accepters', 'identity accepters, consequence resisters' and 'accepters'. Participants offered varying accounts of the degree of personal responsibility that needed to be assumed in response to the diagnosis. Preferences for different styles of education were also expressed, with many reporting that they enjoyed and benefited from group education, although some reported ambivalence or disappointment with their experiences of education. It was difficult to identify striking thematic differences between accounts of people on different arms of the trial, although there was some very tentative evidence that those who attended DESMOND were more accepting of a changed identity and its implications for their management of diabetes. No one single approach to education is likely to suit all people newly diagnosed with diabetes, although structured group education may suit many. This paper identifies varying orientations and preferences of people with diabetes towards forms of both education and self-management, which should be taken into account when planning approaches to education.


A novel fatty acid profile index--the lipophilic index--and risk of myocardial infarction.
The lipophilic index (LI), a mean measure of fatty acid melting points, has been proposed to capture overall fatty acid profile and may play an important role in the etiology of coronary heart disease. We aimed to determine the association between LI in diet and in adipose tissue and metabolic risk factors for myocardial infarction (MI) and risk of MI. We used a population-based, matched case-control study of nonfatal first acute MI conducted in Costa Rica between 1994 and 2004, with 1,627 case-control pairs. The LI is defined as the mean of the melting points of specific fatty acids in diet or adipose tissue. LIs in diet and adipose tissue were significantly associated with higher plasma triglyceride concentrations, low-density lipoprotein cholesterol concentrations, and low-density:high-density lipoprotein cholesterol ratio. Comparing extreme quintiles for the LI in diet or adipose tissue, the odds ratios for MI were 1.57 (95% confidence interval: 1.22, 2.02; P for trend < 0.001) for dietary LI and 1.30 (95% confidence interval: 1.00, 1.69; P for trend = 0.02) for adipose tissue LI in the multivariable models. We hypothesize that a higher LI in diet and in adipose tissue represents decreased fatty acid fluidity and could play an important role in the etiology of coronary heart disease.


The pharmacological and non-pharmacological interventions for the management of fatigue related multiple sclerosis.
The clinical aim was to provide up-to-date evidence-based recommendations for the treatment of MS-related fatigue (MSRF). The scientific aim was to prioritise topics for future randomised clinical trials with sufficient power. A systematic search of review based research that considered MSRF in adults (18years and over) was undertaken in May 2016. Data from reviews was extracted, critically appraised and synthesised using four specific techniques. A total of 24 reviews were identified (17 non-pharmacological, 5 pharmacological, 2 combining both), which contained 339 studies on interventions deigned to improve MSRF. The methodological quality of the reviews was identified by an average AMSTAR score of 6.5 (SD=1.87: 95% CI=5.75-7.25). No pharmacological intervention had strong evidence for improving MSRF. Limited/conflicting evidence was found for Amantadine and Prokarin and potential benefits for Modafinil were identified. Pemoline and Carnitine contained unclear/no evidence for fatigue management. Non-pharmacological interventions produced mixed conclusions regarding the effectiveness of the intervention to improve MSRF. Education (energy conservation and fatigue management) and exercise had supporting evidence for reducing MSRF but mixed conclusions gathered from subtypes of exercise. Reviews considering psycho-behavioural interventions (CBT and mindfulness) had limited information considering effectiveness. Finally, a single intervention combining physical and cognitive strategies showed more promising results. Further research into Pharmacological interventions for MSRF is required notably considering the potential of Modafinil. Yoga and energy conservation/fatigue management programs had strong evidence supporting use in management of MSRF. Due to the dissimilar interventions used in combined training the subtype of exercise cannot be recommended. Future research into Amantadine, psycho-behavioural interventions is vital to justify the current National Institute for Health and Care Excellence guidelines. The methodological quality of studies inhibited the ability of this review to provide other recommendations.


Modeling epileptic spasms during infancy: Are we heading for the treatment yet?
Infantile spasms (IS or epileptic spasms during infancy) were first described by Dr. William James West (aka West syndrome) in his own son in 1841. While rare by definition (occurring in 1 per 3200-3400 live births), IS represent a major social and treatment burden. The etiology of IS varies - there are many (>200) different known pathologies resulting in IS and still in about one third of cases there is no obvious reason. With the advancement of genetic analysis, role of certain genes (such as ARX or CDKL5 and others) in IS appears to be important. Current treatment strategies with incomplete efficacy and serious potential adverse effects include adrenocorticotropin (ACTH), corticosteroids (prednisone, prednisolone) and vigabatrin, more recently also a combination of hormones and vigabatrin. Second line treatments include pyridoxine (vitamin B6) and ketogenic diet. Additional treatment approaches use rapamycin, cannabidiol, valproic acid and other anti-seizure medications. Efficacy of these second line medications is variable but usually inferior to hormonal treatments and vigabatrin. Thus, new and effective models of this devastating condition are required for the search of additional treatment options as well as for better understanding the mechanisms of IS. Currently, eight models of IS are reviewed along with the ideas and mechanisms behind these models, drugs tested using the models and their efficacy and usefulness. Etiological variety of IS is somewhat reflected in the variety of the models. However, it seems that for finding precise personalized approaches, this variety is necessary as there is no "one-size-fits-all" approach possible for both IS in particular and epilepsy in general.


Interfacial motion in flexo- and order-electric switching between nematic filled states.
We consider a nematic liquid crystal, in coexistence with its isotropic phase, in contact with a substrate patterned with rectangular grooves. In such a system the nematic phase may fill the grooves without the occurrence of complete wetting. There may exist multiple (meta)stable filled states, each characterized by the type of distortion (bend or splay) in each corner of the groove and by the shape of the nematic-isotropic interface, and additionally the plateaux that separate the grooves may be either dry or wet with a thin layer of nematic. Using numerical simulations, we analyse the dynamical response of the system to an externally-applied electric field, with the aim of identifying switching transitions between these filled states. We find that order-electric coupling between the fluid and the field provides a means of switching between states where the plateaux between grooves are dry and states where they are wetted by a nematic layer, without affecting the configuration of the nematic within the groove. We find that flexoelectric coupling may change the nematic texture in the groove, provided that the flexoelectric coupling differentiates between the types of distortion at the corners of the substrate. We identify intermediate stages of the transitions, and the role played by the motion of the nematic-isotropic interface. We determine quantitatively the field magnitudes and orientations required to effect each type of transition.


Effects of Beetroot Juice on Recovery of Muscle Function and Performance between Bouts of Repeated Sprint Exercise.
This study examined the effects of beetroot juice (BTJ) on recovery between two repeated-sprint tests. In an independent groups design, 20 male, team-sports players were randomized to receive either BTJ or a placebo (PLA) (2 × 250 mL) for 3 days after an initial repeated sprint test (20 × 30 m; RST1) and after a second repeated sprint test (RST2), performed 72 h later. Maximal isometric voluntary contractions (MIVC), countermovement jumps (CMJ), reactive strength index (RI), pressure-pain threshold (PPT), creatine kinase (CK), C-reactive protein (hs-CRP), protein carbonyls (PC), lipid hydroperoxides (LOOH) and the ascorbyl free radical (A(•-)) were measured before, after, and at set times between RST1 and RST2. CMJ and RI recovered quicker in BTJ compared to PLA after RST1: at 72 h post, CMJ and RI were 7.6% and 13.8% higher in BTJ vs. PLA, respectively (p < 0.05). PPT was 10.4% higher in BTJ compared to PLA 24 h post RST2 (p = 0.012) but similar at other time points. No group differences were detected for mean and fastest sprint time or fatigue index. MIVC, or the biochemical markers measured (p > 0.05). BTJ reduced the decrement in CMJ and RI following and RST but had no effect on sprint performance or oxidative stress.


Efficacy and safety of pharmacological and psychological interventions for the treatment of psychosis and schizophrenia in children, adolescents and young adults: a systematic review and meta-analysis.
Studies report contrasting results regarding the efficacy and safety of pharmacological, psychological, and combined interventions in psychosis and schizophrenia in children, adolescents and young adults. Systematic review and meta-analysis. Embase, Medline, PreMedline, PsycINFO, and CENTRAL were searched to July 2013 without restriction to publication status. Randomised trials comparing any pharmacological, psychological, or combined intervention for psychosis and schizophrenia in children, adolescents and young adults were included. Studies were assessed for bias, and GRADE criteria were used to describe the quality of the results. Twenty-seven trials including 3067 participants were identified. Meta-analyses were performed for 12 comparisons: symptoms, relapse, global state, psychosocial functioning, depression, weight and discontinuation. Low quality evidence demonstrated that antipsychotics have small beneficial effects on psychotic symptoms (SMD = -0.42, 95% CI -0.58 to -0.26), and a medium adverse effect on weight gain (WMD = 1.61, 95% CI 0.61 to 2.60) and discontinuation due to side effects (RR = 2.44, 95% CI, 1.12 to 5.31). There were no trials of psychological treatments in under-18 year olds. There was no evidence of an effect of psychological interventions on psychotic symptoms in an acute episode, or relapse rate, but low quality evidence of a large effect for family plus individual CBT on the number of days to relapse (WMD = 32.25, 95% CI -36.52 to -27.98). For children, adolescents and young adults, the balance of risk and benefit of antipsychotics appears less favourable than in adults. Research is needed to establish the potential for psychological treatments, alone and in combination with antipsychotics, in this population.


The fishery performance indicators: a management tool for triple bottom line outcomes.
Pursuit of the triple bottom line of economic, community and ecological sustainability has increased the complexity of fishery management; fisheries assessments require new types of data and analysis to guide science-based policy in addition to traditional biological information and modeling. We introduce the Fishery Performance Indicators (FPIs), a broadly applicable and flexible tool for assessing performance in individual fisheries, and for establishing cross-sectional links between enabling conditions, management strategies and triple bottom line outcomes. Conceptually separating measures of performance, the FPIs use 68 individual outcome metrics--coded on a 1 to 5 scale based on expert assessment to facilitate application to data poor fisheries and sectors--that can be partitioned into sector-based or triple-bottom-line sustainability-based interpretative indicators. Variation among outcomes is explained with 54 similarly structured metrics of inputs, management approaches and enabling conditions. Using 61 initial fishery case studies drawn from industrial and developing countries around the world, we demonstrate the inferential importance of tracking economic and community outcomes, in addition to resource status.


Chemotherapy-induced alopecia: new developments.
Alopecia (hair loss) is one of the most physically and psychologically distressing side effects of cancer chemotherapeutic drugs. Since its first recognition as a common outcome to most chemotherapeutic agents, only a few trials have been reported, using either a method to temporarily reduce the scalp blood flow (scalp tourniquet or hypothermia) or vitamin E, with undocumented and variable efficacy. The lack of progress in the treatment and prevention of chemotherapy-induced alopecia is in part due to the lack of a reproducible animal model. In the past 2 years, we reported on the following observations: (1) treatment of 8-day-old rats with vidarabine (ara-C), doxorubicin, and cyclophosphamide consistently produced either total body alopecia (ara-C and cyclophosphamide) or alopecia confined to the head and proximal part of the back (doxorubicin); (2) Imuvert, a biologic response modifier derived from the bacterium Serratia marcescens, uniformly produced complete protection against alopecia induced by ara-C and doxorubicin but not that produced by cyclophosphamide; (3) the protective effect of Imuvert against chemotherapy-induced alopecia is mediated by a monocyte-mediated cytokine; and (4) this monocyte-derived cytokine is, possibly, interleukin-1. These observations constitute important progress in the understanding and prevention of chemotherapy-induced alopecia.


Neural correlates of true and false memory in mild cognitive impairment.
The goal of this research was to investigate the changes in neural processing in mild cognitive impairment. We measured phase synchrony, amplitudes, and event-related potentials in veridical and false memory to determine whether these differed in participants with mild cognitive impairment compared with typical, age-matched controls. Empirical mode decomposition phase locking analysis was used to assess synchrony, which is the first time this analysis technique has been applied in a complex cognitive task such as memory processing. The technique allowed assessment of changes in frontal and parietal cortex connectivity over time during a memory task, without a priori selection of frequency ranges, which has been shown previously to influence synchrony detection. Phase synchrony differed significantly in its timing and degree between participant groups in the theta and alpha frequency ranges. Timing differences suggested greater dependence on gist memory in the presence of mild cognitive impairment. The group with mild cognitive impairment had significantly more frontal theta phase locking than the controls in the absence of a significant behavioural difference in the task, providing new evidence for compensatory processing in the former group. Both groups showed greater frontal phase locking during false than true memory, suggesting increased searching when no actual memory trace was found. Significant inter-group differences in frontal alpha phase locking provided support for a role for lower and upper alpha oscillations in memory processing. Finally, fronto-parietal interaction was significantly reduced in the group with mild cognitive impairment, supporting the notion that mild cognitive impairment could represent an early stage in Alzheimer's disease, which has been described as a 'disconnection syndrome'.


A calibration-free electrode compensation method.
In a single-electrode current-clamp recording, the measured potential includes both the response of the membrane and that of the measuring electrode. The electrode response is traditionally removed using bridge balance, where the response of an ideal resistor representing the electrode is subtracted from the measurement. Because the electrode is not an ideal resistor, this procedure produces capacitive transients in response to fast or discontinuous currents. More sophisticated methods exist, but they all require a preliminary calibration phase, to estimate the properties of the electrode. If these properties change after calibration, the measurements are corrupted. We propose a compensation method that does not require preliminary calibration. Measurements are compensated offline by fitting a model of the neuron and electrode to the trace and subtracting the predicted electrode response. The error criterion is designed to avoid the distortion of compensated traces by spikes. The technique allows electrode properties to be tracked over time and can be extended to arbitrary models of electrode and neuron. We demonstrate the method using biophysical models and whole cell recordings in cortical and brain-stem neurons.


Social influence and bullying behavior: intervention-based network dynamics of the fairplayer.manual bullying prevention program.
Bullying is a social phenomenon and although preventive interventions consequently address social mechanisms, evaluations hardly consider the complexity of peer processes. Therefore, the present study analyzes the efficacy of the fairplayer.manual bullying prevention program from a social network perspective. Within a pretest-posttest control group design, longitudinal data were available from 328 middle-school students (MAge = 13.7 years; 51% girls), who provided information on bullying behavior and interaction patterns. The revealed network parameters were utilized to examine the network change (MANCOVA) and the network dynamics (SIENA). Across both forms of analyses, findings revealed the hypothesized intervention-based decrease of bullies' social influence. Hence the present bullying prevention program, as one example of programs that successfully addresses both individual skills and social mechanisms, demonstrates the desired effect of reducing contextual opportunities for the exhibition of bullying behavior.


Effect of high loading on substrate utilization kinetics and microbial community structure in super fast submerged membrane bioreactor.
The study investigated the effect of high substrate loading on substrate utilization kinetics, and changes inflicted on the composition of the microbial community in a superfast submerged membrane bioreactor. Submerged MBR was sequentially fed with a substrate mixture and acetate; its performance was monitored at steady-state, at extremely low sludge age values of 2.0, 1.0 and 0.5d, all adjusted to a single hydraulic retention time of 8.0 h. Each MBR run was repeated when substrate feeding was increased from 200 mg COD/L to 1000 mg COD/L. Substrate utilization kinetics was altered to significantly lower levels when the MBR was adjusted to higher substrate loadings. Molecular analysis of the biomass revealed that variable process kinetics could be correlated with parallel changes in the composition of the microbial community, mainly by a replacement mechanism, where newer species, better adapted to the new growth conditions, substituted others that are washed out from the system.


A randomised controlled trial of small particle inhaled steroids in refractory eosinophilic asthma (SPIRA).
Some patients with refractory asthma have evidence of uncontrolled eosinophilic inflammation in the distal airways. While traditional formulations of inhaled steroids settle predominantly in the large airways, newer formulations with an extra-fine particle size have a more peripheral pattern of deposition. Specifically treating distal airway inflammation may improve asthma control. 30 patients with refractory asthma despite high dose inhaled corticosteroids were identified as having persistent airway eosinophilia. Following 2 weeks of prednisolone 30 mg, patients demonstrating an improvement in asthma control were randomised to receive either ciclesonide 320 µg twice daily or placebo in addition to usual maintenance therapy for 8 weeks. The primary outcome measure was sputum eosinophil count at week 8. Alveolar nitric oxide was measured as a marker of distal airway inflammation. There was continued suppression of differential sputum eosinophil counts with ciclesonide (median 2.3%) but not placebo (median 4.5%) though the between-group difference was not significant. When patients who had changed their maintenance prednisolone dose during the trial were excluded the difference between groups was significant (1.4% vs 4.5%, p=0.028). Though alveolar nitric oxide decreased with ciclesonide the value did not reach statistical significance. These data demonstrate that patients with ongoing eosinophilic inflammation are not truly refractory, and that suppression of airway eosinophilia may be maintained with additional inhaled corticosteroid. Further work is needed with a focus on patient-orientated outcome measures such as exacerbation rate, with additional tests of small airway function. NCT01171365. Protocol available at http://www.clinicaltrials.gov.


Management and Complications in Nonoperative Fractures of the Tibial Spine: A Systematic Review.
Effective options exist for acute nonoperative management of anterior tibial spine fractures, yet there exists a paucity of literature describing long-term outcomes for these patients. This systematic review thus aims to consolidate management strategies and complications for patients with nonoperative anterior tibial spine fractures. In accordance with PRISMA guidelines, 5 databases (CINAHL, MEDLINE, EMBASE, Cochrane, and Pubmed) were searched and screened in duplicate. Quality assessment was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. Of 485 studies identified in the initial search, a total of 18 studies involving 369 patients were eligible for this review. These were stratified into 173 type I, 124 type II, and 72 type III injuries as described by Meyers and McKeever. All patients were treated with knee immobilization in either full extension or slight flexion, with possible closed reduction and/or aspiration of hemarthrosis. Complications at final follow-up comprised 33.9% of patients with persistent stiffness, 19.4% persistent instability, 11.1% mechanical symptoms, 6.37 delayed anterior cruciate ligament reconstruction, 4.9% delayed operative intervention for other complications, and 1.9% extension impingement. Given the lack of comparative studies in this review, definitive conclusions for nonoperative management are difficult to establish on the basis of the current body of literature alone. A modestly higher rate of arthrofibrosis and persistent laxity are seen in higher-grade injuries, however, only a minority of studies stratified complications by Meyers and McKeever classification in this review. A better understanding of variables in treatment decision making require further prospective study focused on the collection of functional and patient-reported outcome measures, whereas also further delineating complications by injury severity.


The Timing and Sequence of Cardiovascular Health Decline.
Childhood declines in cardiovascular health have been linked to the development of subclinical atherosclerosis; however, less is known about the timing and sequence of the decline of the specific cardiovascular health components. The study objective is to identify the patterns of decline and associations with adulthood subclinical atherosclerosis. Data were pooled from 5 cardiovascular cohorts. Clinical components of cardiovascular health (BMI, blood pressure, cholesterol, and blood glucose) were categorized as ideal or nonideal using American Heart Association definitions. Multitrajectory models simultaneously fitted the probability ideal for each factor. Adjusted associations between trajectory groups and carotid intima-media thickness were modeled. Data were pooled from December 1, 2015 to June 1, 2019; statistical analysis occurred between June 1, 2019 and June 1, 2020. This study included 9,388 individuals (55% female, 66% White). A total of 5 distinct trajectory groups were created: 1 maintained the ideal levels of all the 4 health factors, 2 had risk onset of a single factor in childhood, 1 had risk onset of multiple factors in childhood, and 1 had risk onset in adulthood. Those with childhood multiple risk onset had 8.1% higher carotid intima-media thickness (95% CI=0.067, 0.095) than those in the ideal group, childhood cholesterol risk onset had 5.9% higher carotid intima-media thickness (95% CI=0.045, 0.072), childhood BMI risk onset had 5.5% higher carotid intima-media thickness (95% CI=0.041, 0.069), and early adulthood multiple risk onset had 2.7% higher carotid intima-media thickness (95% CI=0.013, 0.041). Those who lost the ideal status of cardiovascular health in childhood and early adulthood had more subclinical atherosclerosis than those who retained the ideal cardiovascular health across the life course, underscoring the importance of preserving the ideal cardiovascular health beginning in childhood and continued into adulthood.


A trial of retrofitted advisory collision avoidance technology in government fleet vehicles.
In-vehicle collision avoidance technology (CAT) has the potential to prevent crash involvement. In 2015, Transport for New South Wales undertook a trial of a Mobileye 560 CAT system that was installed in 34 government fleet vehicles for a period of seven months. The system provided headway monitoring, lane departure, forward collision and pedestrian collision warnings, using audio and visual alerts. The purpose of the trial was to determine whether the technology could change the driving behaviour of fleet vehicle drivers and improve their safety. The evaluation consisted of three components: (1) analysis of objective data to examine effects of the technology on driving behaviour, (2) analysis of video footage taken from a sample of the vehicles to examine driving circumstances that trigger headway monitoring and forward collision warnings, and (3) a survey completed by 122 of the 199 individuals who drove the trial vehicles to examine experiences with, and attitudes to, the technology. Analysis of the objective data found that the system resulted in changes in behaviour with increased headway and improved lane keeping, but that these improvements dissipated once the warning alerts were switched off. Therefore, the system is capable of altering behaviour but only when it is actively providing alerts. In-vehicle video footage revealed that over a quarter of forward collision warnings were false alarms, in which a warning event was triggered despite there being no vehicle travelling ahead. The surveyed drivers recognised that the system could improve safety but most did not wish to use it themselves as they found it to be distracting and felt that it would not prevent them from having a crash. The results demonstrate that collision avoidance technology can improve driving behaviour but drivers may need to be educated about the potential benefits for their driving in order to accept the technology.


Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat.
Several lines of evidence demonstrate that inhaled nitric oxide (iNO) not only acts locally on the pulmonary vasculature but also has remote effects on the mature and developing brain under basal or pathological conditions by modulating cerebral blood flow and microvascularization, white matter maturation, inflammation, and subsequent brain repair. Previously, consistent studies demonstrated that increased levels of guanosine 3',5' cyclic monophosphate (cGMP), the main effector of biological effect induced by nitric oxide (NO), significantly augment proliferation and neuronal differentiation of adult neural progenitor cells (NPCs). In the present study, we ask the question whether iNO could promote the proliferation of NPCs in the uninjured developing brain. We first reported that iNO exposure at a concentration of 20 ppm during the first 7 days of life was associated with a significant but transient elevation of brain cGMP concentration 2 h after the onset of iNO exposure and a subsequent increase in myelin content of the developing white matter at postnatal day (P) 10. Using BrDu labelling and colabelling with specific cell-type markers we found that iNO exposure of rat pups results in an increased NPC proliferation in several layers of the subventricular zone (SVZ) at both early (30 h) and late (P7) time points. These proliferating NPCs were found to be sustainably viable and subsequently differentiated into oligodendroglial cells in the developing white matter and cortex. We also found that NG2 immunoreactivity around vessel walls, labeling pericyte cells, was increased in NO-exposed rat pups in the periventricular SVZ. In conclusion, iNO appears to act on oligodendrocyte progenitor cells, leading to increased density of mature oligodendrocytes and myelin content in the immature rat brain.


Genomic tests for ovarian cancer detection and management.
To assess the evidence that the use of genomic tests for ovarian cancer screening, diagnosis, and treatment leads to improved outcomes. PubMed and reference lists of recent reviews. We evaluated tests for: (a) single gene products; (b) genetic variations affecting risk of ovarian cancer; (c) gene expression; and (d) proteomics. For tests covered in recent evidence reports (cancer antigen 125 [CA-125] and breast cancer genes 1 and 2 [BRCA1/2]), we added studies published subsequent to the reports. We sought evidence on: (a) the analytic performance of tests in clinical laboratories; (b) the sensitivity and specificity of tests in different patient populations; (c) the clinical impact of testing in asymptomatic women, women with suspected ovarian cancer, and women with diagnosed ovarian cancer; (d) the harms of genomic testing; and (e) the impact of direct-to-consumer and direct-to-physician advertising on appropriate use of tests. We also constructed a computer simulation model to test the impact of different assumptions about ovarian cancer natural history on the relative effectiveness of different strategies. There are reasonable data on the clinical laboratory performance of most radioimmunoassays, but the majority of the data on other genomic tests comes from research laboratories. Genomic test sensitivity/specificity estimates are limited by small sample sizes, spectrum bias, and unrealistically large prevalences of ovarian cancer; in particular, estimates of positive predictive values derived from most of the studies are substantially higher than would be expected in most screening or diagnostic settings. We found no evidence relevant to the question of the impact of genomic tests on health outcomes in asymptomatic women. Although there is a relatively large literature on the association of test results and various clinical outcomes, the clinical utility of changing management based on these results has not been evaluated. We found no evidence that genomic tests for ovarian cancer have unique harms beyond those common to other tests for genetic susceptibility or other tests used in screening, diagnosis, and management of ovarian cancer. Studies of a direct-to-consumer campaign for BRCA1/2 testing suggest increased utilization, but the effect on "appropriateness" was unclear. Model simulations suggest that annual screening, even with a highly sensitive test, will not reduce ovarian cancer mortality by more than 50 percent; frequent screening has a very low positive predictive value, even with a highly specific test. Although research remains promising, adaptation of genomic tests into clinical practice must await appropriately designed and powered studies in relevant clinical settings.


The endocannabinoid system.
Thirty years ago, the discovery of a cannabinoid (CB) receptor that interacts with the psychoactive compound in Cannabis led to the identification of anandamide, an endogenous receptor ligand or endocannabinoid. Research on endocannabinoids has since exploded, and additional receptors along with their lipid mediators and signaling pathways continue to be revealed. Specifically, in humans, the release of endocannabinoids from membrane lipids occurs on demand and the signaling process is rapidly attenuated by the breakdown of the ligand suggesting a tight regulation of the endocannabinoid system (ECS). Additionally, the varying distribution of CB receptors between the central nervous system and other tissues allows for the ECS to participate in a wide range of cognitive and physiological processes. Select plant-derived 'phyto'cannabinoids such as Δ-9-tetrahydrocannabinol (Δ9-THC) bind to the CB receptors and trigger the ECS, and in the case of Δ9-THC, while it has therapeutic value, can also produce detrimental effects. Current research is aimed at the identification of additional phytocannabinoids with minimal psychotropic effects with potential for therapeutic development. Although decades of research on the ECS and its components have expanded our understanding of the mechanisms and implications of endocannabinoid signaling in mammals, it continues to evolve. Here, we provide a brief overview of the ECS and its overlap with other related lipid-mediated signaling pathways.


Effects of portal versus systemic venous drainage in pancreas and kidney-pancreas transplantation.
We performed a retrospective analysis to compare pancreas transplantation with systemic-enteric drainage (SE) or portal-enteric drainage (PE). We reviewed 38 consecutive pancreas transplants including 31 simultaneous kidney-pancreas (SKP) and 7 pancreas after kidney (PAK), using either systemic (n = 18) or portal (n = 20) venous drainage. Demographic, clinical, and immunologic variables were similar for both groups. There were no significant differences in patient, kidney, or pancreas allograft survival rates after a mean follow-up of 23 months (range 1-60). The mean length of hospital stay within 3 months was 34 days among the SE group versus 20 days in the PE group (P = ns). The incidences of intraabdominal infection, early relaparotomy, and acute rejection episodes were not different between groups. The blood pressure levels were similar among the SE and PE groups. There was no significant difference in creatinine, or fasting glucose, C-peptide, cholesterol, or triglyceride levels or homeostatic model assessment (HOMA) beta cell, HOMA-S, and HOMA-IR index. HbA1c was lower at 6 and 12 months in the PE group (P < .05). Mean prednisone and mycophenolate mofetil doses as well as tacrolimus levels were identical for both groups. The results suggested sustained long-term endocrine function in both groups, showing that in the short term, portal venous drainage did not offer major metabolic or immunologic advantages compared with systemic delivery of insulin.


Krill Oil Supplementation Improves Dyslipidemia and Lowers Body Weight in Mice Fed a High-Fat Diet Through Activation of AMP-Activated Protein Kinase.
Krill oil is a novel, commercially available marine oil rich in long-chain polyunsaturated omega-3 fatty acids, particularly eicosapentaenoic acid and docosahexaenoic acid. Compared with fish oil, the effects of krill oil supplementation on human health and its underlying action mechanisms are currently poorly understood. In the present study, we examined the effect of krill oil supplementation on metabolic parameters of mice fed a high-fat diet (HFD). Krill oil supplementation in mice fed a HFD for 10 weeks resulted in an ∼15% lower body weight gain and a dramatic suppression of hepatic steatosis. These effects were associated with significantly lower serum triglyceride and low-density lipoprotein-cholesterol levels. We further uncovered a novel underlying mechanism, showing that AMP-activated protein kinase, a master regulator of glucose and lipid metabolism, mediates the beneficial effects of krill oil.


Self-rated depressive symptoms in medical inpatients: age and racial differences.
One thousand and eleven men under age forty (n = 161) or over age sixty-four (n = 850) admitted to medical and neurological services of an acute care hospital were screened for depressive symptoms as part of the Durham VA Mental Health Survey. Thirty-three percent of younger and 22 percent of older men scored 11 or higher on the Geriatric Depression Scale. Self-rated symptoms were most prevalent among younger whites (40%) and least common in older blacks (19%). Other exogenous factors such as being retired or unemployment and prior psychiatric history were also related to depressive symptoms, as were poor functional status, impaired cognitive status, and respiratory illness. Coping resources associated with fewer symptoms were social support and moderate alcohol use. In a subgroup of 443 patients, self-rated symptoms were compared with observer-rated symptoms. Agreement was highest among young Whites and lowest in older Blacks. Other correlates also varied depending on whether self-rated or observer-rated symptoms were considered. We conclude that self-rated symptoms are common among medical inpatients, are linked with and confounded by certain health and sociodemographic factors, and may be relatively insensitive as a measure of depression in elderly blacks.


L-asparaginase as a marker of chemotherapy dose modification in children with acute lymphoblastic leukemia.
The objective of the current study was to compare chemotherapy dose modifications in obese (a body mass index [BMI] > 95%) and nonobese (a BMI < or = 95%) pediatric patients with acute lymphoblastic leukemia (ALL). The study cohort was comprised of 199 pediatric patients diagnosed with ALL who were treated at 1 of 2 South Texas pediatric oncology centers between 1990-2000. The relative chemotherapy dose modification during the induction phase of chemotherapy was calculated as the ratio of 1) the actual administered dose of L-asparaginase and 2) the protocol-calculated dose of L-asparaginase. The extent to which the chemotherapy dose modification varied according to obesity status was assessed using stratified Student t tests and an ordinary least-squares regression analysis. Obese ALL patients were found to exhibit a 7% decrease in the mean relative modification of L-asparaginase during induction chemotherapy compared with their nonobese counterparts. This finding was statistically significant (P = 0.009), even after adjustment for gender, age, ethnicity, and clinical institution. To the authors' knowledge, the current study is the first published report of an obesity-associated chemotherapy dose modification in pediatric patients with ALL, the most common childhood malignancy. It will be important to examine whether these findings are consistent with those observed in future studies, and ultimately to assess the association between obesity-related dose modifications and long-term cancer outcomes.


Dyskeratosis congenita associated with leukoplakia of the tongue.
Dyskeratosis congenita (DC) is an inherited disease characterized by the triad of skin pigmentation, nail dystrophy, and oral leukoplakia. Among other abnormalities, bone marrow failure and a predisposition to cancer are recognized as the major causes of premature mortality in patients with DC. This disease is associated with short telomeres and mutations in 10 genes associated with telomerase and telomere components. The case of a 35-year-old male patient diagnosed with DC, who presented with leukoplakia of the tongue and had a high degree of hypoplastic marrow, but no haematological abnormalities, is reported here. The diagnosis of DC was confirmed by detection of short telomeres in the blood cells and mutations in the DKC1 gene. This encounter with the case presented suggests that an awareness of the classical forms of DC is important for oral clinicians so that an early diagnosis can be made and the patient can be managed appropriately. Furthermore, genetic analysis is necessary to establish the diagnosis of DC.


Impact of sickle cell disease on patients' daily lives, symptoms reported, and disease management strategies: Results from the international Sickle Cell World Assessment Survey (SWAY).
Sickle cell disease (SCD) is a genetic disorder, characterized by hemolytic anemia and vaso-occlusive crises (VOCs). Data on the global SCD impact on quality of life (QoL) from the patient viewpoint are limited. The international Sickle Cell World Assessment Survey (SWAY) aimed to provide insights into patient-reported impact of SCD on QoL. This cross-sectional survey of SCD patients enrolled by healthcare professionals and advocacy groups assessed disease impact on daily life, education and work, symptoms, treatment goals, and disease management. Opinions were captured using a Likert scale of 1-7 for some questions; 5-7 indicated "high severity/impact." Two thousand one hundred and forty five patients (mean age 24.7 years [standard deviation (SD) = 13.1], 39% ≤18 years, 52% female) were surveyed from 16 countries (six geographical regions). A substantial proportion of patients reported that SCD caused a high negative impact on emotions (60%) and school achievement (51%) and a reduction in work hours (53%). A mean of 5.3 VOCs (SD = 6.8) was reported over the 12 months prior to survey (median 3.0 [interquartile range 2.0-6.0]); 24% were managed at home and 76% required healthcare services. Other than VOCs, fatigue was the most commonly reported symptom in the month before survey (65%), graded "high severity" by 67% of patients. Depression and anxiety were reported by 39% and 38% of patients, respectively. The most common patient treatment goal was improving QoL (55%). Findings from SWAY reaffirm that SCD confers a significant burden on patients, epitomized by the high impact on patients' QoL and emotional wellbeing, and the high prevalence of self-reported VOCs and other symptoms.


Perceptions of Community Health Workers (CHWs/PS) in the U.S.-Mexico border HEART CVD study.
Although prior research has shown that Community Health Workers/Promotores de Salud (CHW/PS) can facilitate access to care, little is known about how CHW/PS are perceived in their community. The current study reports the findings of a randomized telephone survey conducted in a high-risk urban community environment along the U.S.-Mexico border. In preparation for a community-based CHW/PS intervention called the HEART ecological study, the survey aimed to assess perceptions of CHW/PS, availability and utilization of community resources (recreational and nutrition related) and health behaviors and intentions. A total of 7,155 calls were placed to complete 444 surveys in three zip codes in El Paso, Texas. Results showed that participants felt that healthful community resources were available, but utilization was low and variable: 35% reported going to a park, 20% reported having taken a health class, few reported using a gym (12%), recreation center (8%), or YMCA/YWCA (0.9%). Awareness and utilization of CHW/PS services were low: 20% of respondents had heard of CHW/PS, with 8% reporting previous exposure to CHW/PS services. Upon review of a definition of CHW/PS, respondents expressed positive views of CHW/PS and their value in the healthcare system. Respondents who had previous contact with a CHW/PS reported a significantly more positive perception of the usefulness of CHW/PS (p = 0.006), were more likely to see CHW/PS as an important link between providers and patients (p = 0.008), and were more likely to ask a CHW/PS for help (p = 0.009). Participants who utilized CHW/PS services also had significantly healthier intentions to reduce fast food intake. Future research is needed to evaluate if CHW/PS can facilitate utilization of available community resources such as recreational facilities among Hispanic border residents at risk for CVD.


A qualitative study of systemic influences on paramedic decision making: care transitions and patient safety.
Paramedics routinely make critical decisions about the most appropriate care to deliver in a complex system characterized by significant variation in patient case-mix, care pathways and linked service providers. There has been little research carried out in the ambulance service to identify areas of risk associated with decisions about patient care. The aim of this study was to explore systemic influences on decision making by paramedics relating to care transitions to identify potential risk factors. An exploratory multi-method qualitative study was conducted in three English National Health Service (NHS) Ambulance Service Trusts, focusing on decision making by paramedic and specialist paramedic staff. Researchers observed 57 staff across 34 shifts. Ten staff completed digital diaries and three focus groups were conducted with 21 staff. Nine types of decision were identified, ranging from emergency department conveyance and specialist emergency pathways to non-conveyance. Seven overarching systemic influences and risk factors potentially influencing decision making were identified: demand; performance priorities; access to care options; risk tolerance; training and development; communication and feedback and resources. Use of multiple methods provided a consistent picture of key systemic influences and potential risk factors. The study highlighted the increased complexity of paramedic decisions and multi-level system influences that may exacerbate risk. The findings have implications at the level of individual NHS Ambulance Service Trusts (e.g. ensuring an appropriately skilled workforce to manage diverse patient needs and reduce emergency department conveyance) and at the wider prehospital emergency care system level (e.g. ensuring access to appropriate patient care options as alternatives to the emergency department).


No advantage of quadruple- or triple-class antiretroviral therapy as initial treatment in patients with very high viraemia.
We assessed whether quadruple or triple-class therapy for the initial treatment of HIV-1 infection provides a virological benefit over standard triple therapy in patients with very high plasma viraemia. The assessment was made based on a national observational HIV cohort in the Netherlands. Inclusion criteria were age ≥18 years, treatment-naive, plasma viral load (pVL) ≥500,000 copies/ml and initiation of quadruple or triple therapy between 2001 and 2011. Time to viral suppression, defined as pVL<50 copies/ml, was compared between the two groups using Kaplan-Meier plots and multivariate Cox regression analysis. A total of 675 patients were included: 125 (19%) initiated quadruple and 550 (81%) triple therapy. Median pVL was 5.9 (IQR 5.8-6.1) log(10) copies/ml in both groups (P=0.49). 22 (18%) patients on quadruple and 63 (12%) on triple therapy interrupted the treatment regimen because of drug-related toxicity (P=0.06). Median time to viral suppression was 5.8 (IQR 4.6-7.9) and 6.0 (4.0-9.4) months in the patients on quadruple and triple therapy, respectively (log-rank, P=0.42). In the adjusted Cox analysis, quadruple therapy was not associated with time to viral suppression (HR 1.07 [95% CI 0.86, 1.33], P=0.53). Similar results were seen when comparing triple- versus dual-class therapy (n=72 versus n=601, respectively). Initial quadruple- or triple-class therapy was equally effective as standard triple therapy in the suppression of HIV-1 in treatment-naive patients with very high viraemia and did not result in faster pVL decreases, but did expose patients to additional toxicity.


Reconstitution and structural analysis of the yeast box H/ACA RNA-guided pseudouridine synthase.
Box H/ACA ribonucleoprotein particles (RNPs) mediate pseudouridine synthesis, ribosome formation, and telomere maintenance. The structure of eukaryotic H/ACA RNPs remains poorly understood. We reconstituted functional Saccharomyces cerevisiae H/ACA RNPs with recombinant proteins Cbf5, Nop10, Gar1, and Nhp2 and a two-hairpin H/ACA RNA; determined the crystal structure of a Cbf5, Nop10, and Gar1 ternary complex at 1.9 Å resolution; and analyzed the structure-function relationship of the yeast complex. Although eukaryotic H/ACA RNAs have a conserved two-hairpin structure, isolated single-hairpin RNAs are also active in guiding pseudouridylation. Nhp2, unlike its archaeal counterpart, is largely dispensable for the activity, reflecting a functional adaptation of eukaryotic H/ACA RNPs to the variable RNA structure that Nhp2 binds. The N-terminal extension of Cbf5, a hot spot for dyskeratosis congenita mutation, forms an extra structural layer on the PUA domain. Gar1 is distinguished from the assembly factor Naf1 by containing a C-terminal extension that controls substrate turnover and the Gar1-Naf1 exchange during H/ACA RNP maturation. Our results reveal significant novel features of eukaryotic H/ACA RNPs.


The lung-specific proteome defined by integration of transcriptomics and antibody-based profiling.
The combined action of multiple cell types is essential for the physiological function of the lung, and increased awareness of the molecular constituents characterizing each cell type is likely to advance the understanding of lung biology and disease. In the current study, we used genome-wide RNA sequencing of normal lung parenchyma and 26 additional tissue types, combined with antibody-based protein profiling, to localize the expression to specific cell types. Altogether, 221 genes were found to be elevated in the lung compared with their expression in other analyzed tissues. Among the gene products were several well-known markers, but also several proteins previously not described in the context of the lung. To link the lung-specific molecular repertoire to human disease, survival associations of pneumocyte-specific genes were assessed by using transcriptomics data from 7 non-small-cell lung cancer (NSCLC) cohorts. Transcript levels of 10 genes (SFTPB, SFTPC, SFTPD, SLC34A2, LAMP3, CACNA2D2, AGER, EMP2, NKX2-1, and NAPSA) were significantly associated with survival in the adenocarcinoma subgroup, thus qualifying as promising biomarker candidates. In summary, based on an integrated omics approach, we identified genes with elevated expression in lung and localized corresponding protein expression to different cell types. As biomarker candidates, these proteins may represent intriguing starting points for further exploration in health and disease.


Virus-triggered autophagy in viral hepatitis - possible novel strategies for drug development.
Autophagy is a very tightly regulated process that is important in many cellular processes including development, differentiation, survival and homoeostasis. The importance of this process has already been proven in numerous common diseases such as cancer and neurodegenerative disorders. Emerging data indicate that autophagy plays an important role in some liver diseases including liver injury induced by ischaemia reperfusion and alpha-1 antitrypsin Z allele-dependent liver disease. Autophagy may also occur in viral infection, and it may play a crucial role in antimicrobial host defence against pathogens, while supporting cellular homoeostasis processes. Here, the latest findings on the role of autophagy in viral hepatitis B and C infection, which are both serious health threats, will be reviewed.


Testing the Pagan Prescription: Using a Randomized Controlled Trial to Investigate Pagan Spell-Casting as a Form of Noncontact Healing.
Objectives: This research investigates the healing practices of modern Paganism using a randomized controlled trial. Paganism is a burgeoning belief system in the United Kingdom, within which healing is a key aspect. However, Pagan spell-casting practices have received little attention from distance healing researchers. This study aims to address this gap in the literature. Design: This study utilized a randomized, double-blind, delayed intervention design. Settings/Location: Research took place at the University of Northampton. Subjects: Forty-four participants (30 females, 14 males) were recruited using snowball sampling (mean age = 24.30; range = 18-55). Procedure: Participants were randomly allocated to either Group A or B. Participants made written requests to the practitioner about changes they would like to see in their lives and provided a photograph and personal item to be used during the intervention. Participants attended meetings once a week during which they would take part in a guided body scan meditation before completing a quality-of-life measure. Healing practices were conducted for Group A between weeks 1 and 2 and for Group B between weeks 2 and 3. Outcome Measure: Well-being was measured using the 26-item WHOQOL-BREF. Results: Multivariate analysis of variance (MANOVA) showed a significant, positive change in general health from weeks 1 to 4 (F = 4.02, p = 0.025, η2 = 0.149). Separate analysis of variances of the four WHOQOL domains showed significant improvements across the study in the physical and psychologic domains only; there was no significant group difference on any of the outcomes. Conclusion: All participants showed an increase in health and well-being domains directly related to their spell requests. However, there are no group differences to suggest that the spell-casting intervention was responsible.


Defect in negative selection in lpr donor-derived T cells differentiating in non-lpr host thymus.
Transplantation of bone marrow cells of lpr/lpr mice into irradiated normal mice fails to develop massive lymphadenopathy or autoimmunity but causes severe graft-vs.-host-like syndrome. To elucidate an abnormality of lpr/lpr bone marrow-derived T cells, we transplanted bone marrow cells of Mlsb lpr/lpr mice into H-2-compatible Mlsa non-lpr mice. Although lpr/lpr T cell precursors repopulated the host thymus as well as +/+ cells, a proportion of CD4+CD8+ cells decreased, and that of both CD4- and CD8- single-positive cells increased compared with those of +/+ recipients. Notably, in MRL/lpr----AKR and C3H/lpr----AKR chimeras, CD4 single-positive thymocytes contained an increased number of V beta 6+ cells in spite of potentially deleting alleles of Mlsa, whereas V beta 6+ mature T cells were deleted in the MRL/+ ----AKR and C3H/+ ----AKR chimeras. There was no difference between MRL/+ ----AKR and MRL/lpr----AKR chimeras in their proportion of V beta 3+ cells because both host and donor strain lack the deleting alleles. Interleukin 2 receptor expression of mature T cells, in the thymus and lymph node, was obviously higher in the MRL/lpr----AKR chimeras, in particular in the "forbidden" V beta 6+ subset. Moreover, lpr donor-derived peripheral T cells showed vigorous anti-CD3 response. These results indicate that lpr-derived T cells escape not only tolerance-related clonal deletion but also some induction of unresponsiveness in the non-lpr thymus.


Outcome of pregnancy in women with cystic fibrosis.
As women with cystic fibrosis are living longer, pregnancy is becoming increasingly common. The combined experience of pregnancies in women with cystic fibrosis from adult centres in the Midlands and North of England has been examined. A retrospective study of the case notes of 22 pregnancies in 20 patients with cystic fibrosis examined changes in lung function, body weight, and microbiological status during the course of pregnancy. Duration of pregnancy, birth weight, and maternal survival were amongst other variables studied. The relation between values before pregnancy and important outcome measures were examined. Eighteen of 22 pregnancies were completed producing healthy, non-cystic fibrosis infants (12 female). Mothers lost 13% of FEV1 and 11% of FVC during pregnancy, most of which was regained. Body weight changes were variable, but most mothers gained weight (mean weight gain 5.7 kg). Microbiological status remained unchanged. Six infants were preterm and two were light for dates. Four mothers died up to 3.2 years following delivery. Of the prepregnancy parameters examined, %FEV1 showed the best correlation with maternal weight gain, gestation, birth weight, and maternal survival. Pregnancy was well tolerated by most mothers with cystic fibrosis although those with moderate to severe lung disease (%FEV1 < 60%) before pregnancy fared worse, producing preterm infants and suffering increased loss of lung function and mortality compared with mildly affected mothers. Prepregnancy %FEV1 appears to be the most useful predictor of important outcome measures in pregnancies in women with cystic fibrosis.


Skin cancer chemoprevention with systemic retinoids: an adjunct in the management of selected high-risk patients.
Systemic retinoids (isotretinoin, etretinate, and acitretin) have been shown to be effective chemotherapeutic agents in studies of patients with xeroderma pigmentosum, the nevoid basal cell carcinoma syndrome, and recipients of organ or bone marrow transplantation. In addition, patients who do not have these disorders but who are actively developing large numbers of new skin cancers may also benefit from this approach. All patients developing large numbers of skin cancers need rigorous UV protection and frequent dermatologic examinations. Although isotretinoin and acitretin share overlapping toxicities, there are differences that may affect drug choice. Because low doses may be effective, there are advantages to beginning treatment at a low dose, and subsequently, increasing dose if necessary, based on patient response. Laboratory monitoring including pregnancy testing should be performed before and during treatment. Long-term toxicity, primarily involving the skeletal system, can be monitored with imaging studies.


Methane emissions: choosing the right climate metric and time horizon.
Methane is a more potent greenhouse gas (GHG) than CO2, but it has a shorter atmospheric lifespan, thus its relative climate impact reduces significantly over time. Different GHGs are often conflated into a single metric to compare technologies and supply chains, such as the global warming potential (GWP). However, the use of GWP is criticised, regarding: (1) the need to select a timeframe; (2) its physical basis on radiative forcing; and (3) the fact that it measures the average forcing of a pulse over time rather than a sustained emission at a specific end-point in time. Many alternative metrics have been proposed which tackle different aspects of these limitations and this paper assesses them by their key attributes and limitations, with respect to methane emissions. A case study application of various metrics is produced and recommendations are made for the use of climate metrics for different categories of applications. Across metrics, CO2 equivalences for methane range from 4-199 gCO2eq./gCH4, although most estimates fall between 20 and 80 gCO2eq./gCH4. Therefore the selection of metric and time horizon for technology evaluations is likely to change the rank order of preference, as demonstrated herein with the use of natural gas as a shipping fuel versus alternatives. It is not advisable or conservative to use only a short time horizon, e.g. 20 years, which disregards the long-term impacts of CO2 emissions and is thus detrimental to achieving eventual climate stabilisation. Recommendations are made for the use of metrics in 3 categories of applications. Short-term emissions estimates of facilities or regions should be transparent and use a single metric and include the separated contribution from each GHG. Multi-year technology assessments should use both short and long term static metrics (e.g. GWP) to test robustness of results. Longer term energy assessments or decarbonisation pathways must use both short and long-term metrics and where this has a large impact on results, climate models should be incorporated. Dynamic metrics offer insight into the timing of emissions, but may be of only marginal benefit given uncertainties in methodological assumptions.


Bleomycin-induced genome structural variations in normal, non-tumor cells.
Many anticancer drugs are genotoxic agents inducing DNA breaks in actively proliferating cancer cells. However, these same drugs also induce mutations, mostly genome structural variations (GSVs). The detection of GSVs in normal cells and tissues is a major challenge due to the very low abundance of these mutations, which are essentially only detectable in clonal outgrowths, such as tumors. Previously we developed Structural Variant Search (SVS) - an NGS-based assay for the quantitative detection of somatic GSVs in normal cells. Using an improved version of SVS we now demonstrate that the same dose of the anti-cancer drug bleomycin induces about 5 times more somatic GSVs in quiescent primary human fibroblasts than in proliferating cells. GVS induction in non-dividing, normal cells was subsequently confirmed in vivo by demonstrating that a single dose of bleomycin leads to a significant increase of GSV frequency in mouse liver and heart, two postmitotic tissues. Our findings suggest that normal non-cycling differentiated cells may serve as a reservoir of iatrogenically induced mutations. These results provide more insight into the possible molecular mechanisms that underlie late-life morbidities in cancer survivors exposed to chemotherapy.


Aggregates of acetylcholine receptors are associated with plaques of a basal lamina heparan sulfate proteoglycan on the surface of skeletal muscle fibers.
Hybridoma techniques have been used to generate monoclonal antibodies to an antigen concentrated in the basal lamina at the Xenopus laevis neuromuscular junction. The antibodies selectively precipitate a high molecular weight heparan sulfate proteoglycan from conditioned medium of muscle cultures grown in the presence of [35S]methionine or [35S]sulfate. Electron microscope autoradiography of adult X. laevis muscle fibers exposed to 125I-labeled antibody confirms that the antigen is localized within the basal lamina of skeletal muscle fibers and is concentrated at least fivefold within the specialized basal lamina at the neuromuscular junction. Fluorescence immunocytochemical experiments suggest that a similar proteoglycan is also present in other basement membranes, including those associated with blood vessels, myelinated axons, nerve sheath, and notochord. During development in culture, the surface of embryonic muscle cells displays a conspicuously non-uniform distribution of this basal lamina proteoglycan, consisting of large areas with a low antigen site-density and a variety of discrete plaques and fibrils. Clusters of acetylcholine receptors that form on muscle cells cultured without nerve are invariably associated with adjacent, congruent plaques containing basal lamina proteoglycan. This is also true for clusters of junctional receptors formed during synaptogenesis in vitro. This correlation indicates that the spatial organization of receptor and proteoglycan is coordinately regulated, and suggests that interactions between these two species may contribute to the localization of acetylcholine receptors at the neuromuscular junction.


Comparative analyses of plasma amyloid-β levels in heterogeneous and monomerized states by interdigitated microelectrode sensor system.
Detection of amyloid-β (Aβ) aggregates contributes to the diagnosis of Alzheimer disease (AD). Plasma Aβ is deemed a less invasive and more accessible hallmark of AD, as Aβ can penetrate blood-brain barriers. However, correlations between biofluidic Aβ concentrations and AD progression has been tenuous. Here, we introduce a diagnostic technique that compares the heterogeneous and the monomerized states of Aβ in plasma. We used a small molecule, EPPS [4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid], to dissociate aggregated Aβ into monomers to enhance quantification accuracy. Subsequently, Aβ levels of EPPS-treated plasma were compared to those of untreated samples to minimize inter- and intraindividual variations. The interdigitated microelectrode sensor system was used to measure plasma Aβ levels on a scale of 0.1 pg/ml. The implementation of this self-standard blood test resulted in substantial distinctions between patients with AD and individuals with normal cognition (NC), with selectivity and sensitivity over 90%.


Cryptococcus neoformans is a facultative intracellular pathogen in murine pulmonary infection.
To produce chronic infection, microbial pathogens must escape host immune defenses. Infection with the human pathogenic fungus Cryptococcus neoformans is typically chronic. To understand the mechanism by which C. neoformans survives in tissue after the infection of immunocompetent hosts, we systematically studied the course of pulmonary infection in mice by electron microscopy. The macrophage was the primary phagocytic cell at all times of infection, but neutrophils also ingested yeast. Alveolar macrophages rapidly internalized yeast cells after intratracheal infection, and intracellular yeast cells were noted at all times of infection from 2 h through 28 days. However, the proportion of yeast cells in the intracellular and extracellular spaces varied with the time of infection. Early in infection, yeast cells were found predominantly in the intracellular compartment. A shift toward extracellular predominance occurred by 24 h that was accompanied by macrophage cytotoxicity and disruption. Later in infection, intracellular persistence in vivo was associated with replication, residence in a membrane-bound phagosome, polysaccharide accumulation inside cells, and cytotoxicity to macrophages, despite phagolysosomal fusion. Many phagocytic vacuoles with intracellular yeast had discontinuous membranes. Macrophage infection resulted in cells with a distinctive appearance characterized by large numbers of vacuoles filled with polysaccharide antigen. Similar results were observed in vitro using a macrophage-like cell line. Our results show that C. neoformans is a facultative intracellular pathogen in vivo. Furthermore, our observations suggest that C. neoformans occupies a unique niche among the intracellular pathogens whereby survival in phagocytic cells is accompanied by intracellular polysaccharide production.


Head Start Teachers' Professional Development, Well-being, Attitudes, and Practices: Understanding Changes Over Time and Predictive Associations.
Early care and education (ECE) teachers shape children's daily experiences in many ways. Specifically, teachers' well-being, attitudes about child development, and teaching practices are central influences on children's learning. One crucial way ECE programs support teachers to enhance children's learning environments is through the provision of professional development (PD), but little research has examined the PD provided by ECE programs in the absence of focused initiatives to support teachers. In this descriptive study, we use data from a nationally representative study of Head Start teachers (N = 484) to explore whether teachers' job satisfaction, depression, developmentally appropriate attitudes, and frequency of engagement in math and literacy activities are associated with the number of (a) overall PD supports available to teachers, (b) curriculum supports received by teachers, and (c) mentoring supports received by teachers. Many of the associations between teachers' outcomes and overall PD supports, curriculum supports, and mentoring supports were not statistically significant, perhaps because the PD variables do not measure the quality or content of the PD provided. However, those PD supports that were significantly associated with outcomes were associated with specific teacher outcomes in ways consistent with theory, although associations were relatively weak. To contextualize these findings, we describe how PD supports and teachers' outcomes have changed over nearly a decade that encompasses some key Head Start policy changes. This research contributes to our understanding of scalable ways to prepare and support teachers of some of the nation's most vulnerable children.


Mycobacterium chimaera infections associated with heater-cooler units in cardiac surgery.
Mycobacterium chimaera infections following cardiac surgery have been reported from an increasing number of countries. These infections are characterized by a poor prognosis with a case fatality rate around 50% despite treatment. Since the first description in 2013, our understanding has grown steadily. Several outbreak investigations, case series, and experiments with heater-cooler units (HCUs) have been published. This review summarizes the current knowledge. M. chimaera transmission occurs during cardiopulmonary bypass via bioaerosols emitted from contaminated HCU water systems. Manifestations of M. chimaera infection comprise endocarditis, vascular graft infections, surgical site infections, and dissemination. So far, all cases were exposed to a single HCU brand. Samples from the manufacturing site as well as clonality of M. chimaera strains isolated from HCUs and patients suggest a contamination already at time of delivery representing the main source for the outbreak. Nevertheless, HCU contamination in hospitals cannot be excluded. Improved awareness of physicians of M. chimaera infection is crucial to prompt adequate diagnostic workup in patients that have been exposed to HCU presenting with compatible symptoms. For risk mitigation, strict separation between the air volume in contact with HCUs and critical clinical areas such as operating rooms is essential.


Testosterone Retention Mechanism in Sertoli Cells: A Biochemical Perspective.
Mechanism(s) involved in regulating Intratesticular Testosterone levels (iT) have assumed importance in recent years, from the point of view of hormonal contraception. Contraceptives using Testosterone (T) in combination with Progestins (P), for more effective suppression of pituitary gonadotropins thereby iT, are not 100% effective in suppressing spermatogenesis in human males, likely due to pesrsistence of Intratesticular Dihydrotestosterone (iD) in poor-responders. Several lacunae pertaining to the mechanism of action of principal male hormone T during spermatogenesis remain to be resolved. Notably, the mechanism through which T brings about the stage-specific differentiation of germ cells lacking Androgen Receptors (AR). Testosterone is a highly anabolic steroid with a rapid tissue clearance rate. T is intratesticular substrate for synthesis of Dihydrotestosterone (DHT) and Estradiol (E2) involved in spermtaogenesis. Therefore, it is important to delineate the mechanism(s) for retention of iT, in order to understand regulation of its bioavailability in testis. In depth studies, pertaining to the role of androgen-binding protein(s) in sequestration, retention and bioavailability of T/DHT are required to understand male fertility regulation. The appropriate approach to overcome this lacuna would be development of mice lacking functional testicular Androgen-Binding Protein (ABPKO), but not deficient T/DHT, Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH), in order to understand its physiological functions. Insights gained about androgen retention mechanism(s) from the ABPKO murine model will be of immense help in improving the efficacy of male hormonal contraceptives and infertility management.


[Expression of negative emotional responses to the 2011 Great East Japan Earthquake: Analysis of big data from social media].
In this article, we investigated the expression of emotional responses to the 2011 Great East Japan Earthquake by analyzing the frequency of negative emotional terms in tweets posted on Twitter, one of the most popular social media platforms. We focused on differences in time-series variations and diurnal changes between two kinds of disasters: natural disasters (earthquakes and tsunamis) and nuclear accidents. The number of tweets containing negative emotional responses increased sharply shortly after the first huge earthquake and decreased over time, whereas tweets about nuclear accidents showed no correlation with elapsed time. Expressions of anxiety about natural disasters had a circadian rhythm, with a peak at midnight, whereas expressions of anger about the nuclear accident were highly sensitive to critical events related to the accident. These findings were discussed in terms of similarities and differences compared to earlier studies on emotional responses in social media.


LEUNIG has multiple functions in gynoecium development in Arabidopsis.
The Arabidopsis gene LEUNIG was previously found to regulate floral organ identity. In this work we describe gynoecial phenotypes of newly isolated strong leunig alleles, leunig-101, leunig-102, and leunig-103. Gynoecia of these strong leunig mutants are united only at the basal part, leaving four unfused parts at the apex. Among them two medial ones are styles capped with stigmas, and two lateral ones are protrusions from valves. The gynoecium with unfused apex in leunig arises as a unit from a basal meristematic zone, suggesting that LEUNIG is required for normal congenital gynoecium fusion. The epidermal cells on growing inner surfaces of leunig gynoecium failed to fuse after they contact each other, indicating that LEUNIG is essential for the proper postgenital fusion. The epidermal cells at the very distal portion of protruded valves mimic those on wild-type styles, and those valves occasionally also have stigma-like tissues, indicating that LEUNIG function is required for the valve identity determination. We have also analyzed clavata1-4 leunig-101, clavata2-1 lug-101, fruitfull-1 leunig-101, and pinoid-1 leunig-101 double mutants. clavata1-4 leunig-101 and clavata2-1 leunig-101 exhibited additive phenotypes of single mutants, suggesting that LEUNIG and CLAVATA genes function in different pathways. In contrast, FRUITFULL and PINOID genes interact with LEUNIG to regulate gynoecium development. genesis 26:42-54, 2000.


Severe pulmonic valve regurgitation due to histoplasma endocarditis.
A 67-year-old man with myelodysplastic syndrome, disseminated histoplasmosis, and mitral valve replacement presented with dyspnea and peripheral edema. Transthoracic echocardiography demonstrated abnormal pulmonic valve with possible vegetation. Color flow imaging showed laminar flow from main pulmonary artery into right ventricular outflow tract (RVOT) in diastole. The continuous wave Doppler signal showed dense diastolic envelope with steep deceleration slope. These findings were consistent with severe pulmonic valve regurgitation, possibly due to endocarditis. Transesophageal echocardiography demonstrated an echodense mass attached to the pulmonic valve. The mitral valve bioprosthesis appeared intact. Bacterial and fungal blood cultures were negative; however, serum histoplasma antigen was positive. At surgery, the valve appeared destroyed by vegetations. Gomori methenamine silver-stains showed invasive fungal hyphae and yeast consistent with a dimorphic fungus. Valve cultures grew one colony of filamentous fungus. Itraconazole was continued based on expert infectious diseases diagnosis. After surgery, dyspnea and ankle edema resolved. To the best of our knowledge, histoplasma endocarditis of pulmonic valve has not been previously reported. Isolated pulmonic valve endocarditis is rare, accounting for about 2% of infectious endocarditis (IE) cases. Fungi account for about 3% of cases of native valve endocarditis. Characterization of pulmonary valve requires thorough interrogation with 2D and Doppler echocardiography techniques. Parasternal RVOT view allowed visualization of the pulmonary valve and assessment of regurgitation severity. As an anterior structure, it may be difficult to image with transesophageal echocardiography. Mid-esophageal right ventricular inflow-outflow view clearly showed the pulmonary valve and vegetation. Identification and characterization of pulmonary valve abnormalities require thorough interrogation with 2D and Doppler echocardiography techniques.Isolated pulmonary valve IE is rare and requires high index of suspicion. Histoplasma capsulatum IE is rare and requires high index of suspicion.