The Adaptive GameSquad Xbox-Based Physical Activity and Health Coaching Intervention for Youth With Neurodevelopmental and Psychiatric Diagnoses: Pilot Feasibility Study.
The prevalence of neurodevelopmental and psychiatric diagnoses (NPDs) in youth is increasing, and unhealthy physical activity (PA), diet, screen time, and sleep habits contribute to the chronic disease disparities and behavioral challenges this population experiences. This pilot study aims to adapt a proven exergaming and telehealth PA coaching intervention for typically developing youth with overweight or obesity; expand it to address diet, screen, and sleep behaviors; and then test its feasibility and acceptability, including PA engagement, among youth with NPDs. Participants (N=23; mean age 15.1 years, SD 1.5; 17 males, 9 people of color) recruited in person from clinic and special education settings were randomized to the Adaptive GameSquad (AGS) intervention or wait-list control. The 10-week adapted intervention included 3 exergaming sessions per week and 6 real-time telehealth coaching sessions. The primary outcomes included feasibility (adherence to planned sessions), engagement (uptake and acceptability as reported on process questionnaires), and PA level (combined light, moderate, and vigorous as measured by accelerometer). Descriptive statistics summarized feasibility and engagement data, whereas paired, two-tailed t tests assessed group differences in pre-post PA. Of the 6 coaching sessions, AGS participants (n=11; mean age 15.3 years, SD 1.2; 7 males, 4 people of color) completed an average of 5 (83%), averaging 81.2 minutes per week of exergaming. Of 9 participants who completed the exit questionnaire, 6 (67%) reported intention to continue, and 8 (89%) reported feeling that the coaching sessions were helpful. PA and sleep appeared to increase during the course of the intervention over baseline, video game use appeared to decrease, and pre-post intervention PA per day significantly decreased for the control (-58.8 min; P=.04) but not for the intervention group (-5.3 min; P=.77), despite potential seasonality effects. However, beta testers and some intervention participants indicated a need for reduced complexity of technology and more choice in exergames. AGS shows promise in delivering a health behavior intervention remotely to youth with NPDs, but a full-scale efficacy trial with a larger sample size is needed to confirm this finding. On the basis of feedback from beta testers and intervention participants, the next steps should include reduced technology burden and increased exergame choice before efficacy testing. ClinicalTrials.gov NCT03665415; https://clinicaltrials.gov/ct2/show/NCT03665415.


Recurrent hyphema after surgery.
At variable times after anterior segment surgery spontaneous bleeding may occur into the anterior chamber from a gap in the scleral wound. The patient complains of blurred vision in the morning and examination reveals blood in the anterior chamber. Gonioscopy reveals a bleeding point in the scleral would. In the majority of patients the condition is benign and does not require special treatment.


Modulation of the chloride ionophore by benzodiazepine receptor ligands: influence of gamma-aminobutyric acid and ligand efficacy.
t-Butylbicyclophosphorothionate (TBPS) produces dose-dependent enhancement of [3H]propyl beta-carboline-3-carboxylate ([3H]PCC, 40 pM) binding to the benzodiazepine1 (BZ1) receptor subtype in hippocampus. Furthermore, TBPS enhancement of [3H]PCC binding was antagonized by micromolar concentrations of gamma-aminobutyric acid (GABA) in a way reversible by bicuculline. BZ receptor ligands that are "GABA positive" (i.e., enhance GABA neurotransmission) allosterically inhibited [35S]TBPS binding, whereas "GABA-negative" ligands (i.e., inhibit GABA neurotransmission) produced the opposite effect. The efficacy of the ligands as modulators of [35S]TBPS binding was consistent with their reported in vivo pharmacology. The effects of positive and negative ligands on [35S]TBPS binding were modulated by micromolar concentrations of GABA. Examination of the kinetics of [35S]TBPS binding suggested the presence of slowly and rapidly dissociating components. The GABA-positive clonazepam stabilized the rapidly dissociating component of [35S]TBPS binding, whereas methyl beta-carboline-3-carboxylate had a similar effect on the slowly dissociating component. It is speculated that the slowly dissociating component of [35S]TBPS binding is associated with a closed chloride channel, whereas the opposite is proposed for the rapidly dissociating component. The differential effects of GABA-positive versus GABA-negative ligands on [35S]TBPS binding and the modulatory effect of GABA provide further evidence to suggest that [35S]TBPS labels a site near the chloride ionophore linked to the GABA-BZ receptor complex.


Vertical fiber-to-waveguide coupling using adapted fibers with an angled facet fabricated by a simple molding technique.
Vertical coupling between silicon-on-insulator waveguides and optical fibers is achieved using adapted fibers with an angled facet. The proposed coupling scheme is demonstrated for waveguides containing uniform one-dimensional grating couplers. A coupling efficiency of 32% and a 1 dB bandwidth of 32 nm are measured at a wavelength of 1550 nm. We demonstrate single-step fabrication of these fibers using a simple molding technique.


Tumor necrosis factor-alpha, platelet-activating factor, and hydrogen peroxide activate protein kinase C subtypes alpha and epsilon in human saphenous vein endothelial cells.
Protein kinase C (PKC), the major receptor for tumor-promoting phorbol esters, consists of a family of at least 12 distinct lipid-regulated enzymes. We examined the expression and regulation of PKC isoforms in human saphenous vein endothelial cells (HSVEC). Western blot analysis with PKC isoform-specific antibodies indicated that PKC alpha, PKC epsilon and PKC zeta were expressed in these cells. Translocation and down-regulation of PKC alpha and epsilon but not zeta were detected by short-term and long-term treatment with TPA (12-O-tetradecanoylphorbol 13-acetate), respectively. Tumor necrosis factor-alpha (TNF-alpha 1,600 U/ml) and platelet activating factor (PAF 50 nM) increased the membrane content of PKC alpha and epsilon but not zeta. H2O2 (10 mM) induced the translocation of PKC alpha from the cytosol to the membrane and increased PKC epsilon content in both cytosol and membrane. However, 12-(S)-HETE (12-hydroxyeicosatetraenoic acid) (100 nM), a lipoxygenase metabolite of arachidonic acid, did not affect the two isoforms. These results suggest that the molecular action of TNF-alpha, PAF, and H2O2 in HSVEC might occur through PKC alpha and epsilon activation.


Prehospital Vasopressor Use Is Associated with Worse Mortality in Combat Wounded.
Vasopressor medications are frequently used in the management of hypotension secondary to shock. However, little data exists regarding their use in hypotensive trauma patients and their use is controversial. The Department of Defense Trauma Registry was queried from January 2007 to August 2016 using a series of procedural codes to identify eligible casualties, which has been previously described. Mortality was compared between hypotensive casualties with documentation of receipt of vasopressor medications versus casualties not receiving vasopressors. To control for potential confounders, comparisons were repeated by constructing a multivariable logistic regression model that utilized patient category, mechanism of injury, composite injury severity score, total blood products transfused, prehospital heart rate and prehospital systolic pressure. Survival was compared between these groups using propensity matching. Our search strategy yielded 28,222 patients, 124 (0.4%) of whom received prehospital vasopressors. On univariable analysis vasopressor use was associated with lower odds of survival (OR 0.09, 0.06-0.13). The lower odds of survival persisted in the multivariate logistic regression model (OR 0.32, 0.18-0.56). Survival was lower among the vasopressor group (71.3%) when compared to a propensity matched cohort (94.3%). In this dataset, prehospital vasopressor use was associated with lower odds of survival. This finding persisted when adjusting for confounders and in a propensity matched cohort model.


Barriers to technology use among older heart failure individuals in managing their symptoms after hospital discharge.
In North America, heart failure (HF) is the leading cause for hospital readmission. Supportive technology, such as computers and tablets, could potentially assist patients with self-care to manage their condition after hospital discharge; however, older individuals have difficulties in adopting technology to manage their condition. This study used a mixed methods design to identify barriers to technology use in HF self-care. In the qualitative phase, semi-structured interviews were conducted with 18 HF patients and 10 informal caregivers or care partners (CP). In the quantitative phase, five questionnaires were administered to 15 patients and 8 CP: Montreal Cognitive Assessment; Short Literacy Survey and Subjective Numeracy Scale; Self-Care of HF Index; Knowledge Assessment Questionnaire; and Patient Activation Measure. In the qualitative phase, five themes emerged regarding engagement in self care and technology use: knowledge level of HF; level of willingness to ask questions related to HF; confidence level in making health-related decisions individually; level of technology usage in daily activities; and self-recording of health measurements. Quantitative analysis found that most HF patients had mild cognitive impairment (MCI), adequate health numeracy levels to understand and manage their health condition, high confidence levels in managing their condition and willingness to engage in self-care. There was variation in willingness to adopt technology. Patients were willing to engage in HF self-care however they relied on CPs who were more willing to ask questions about HF. Technology tools may assist in HF self-care, but they must be tailored for use among older individuals.


Results of animal experiments with the fourth model of the undulation pump total artificial heart.
Animal experiments using a total artificial heart in a goat are not easy to perform. The fourth model of the undulation pump total artificial heart (UPTAH4), which was designed to perform a long-term physiological experiment including pulsatile and nonpulsatile TAH operations with a conductance- and arterial pressure-based control method named 1/R control, was implanted in 31 goats weighing 38.5 to 60.4 kg (average of 46.8 kg). The 1/R control is a physiological flow control method of TAH developed with a conductance (1/R: reciprocal of a resistance) parallel circuit model. The survival periods were from 0.1 to 153 days (average of 14.5 days). The causes of termination were postoperative bleeding in eight goats, respiratory failure in five goats, device failure in 14 goats, dissected aneurysm in two goats, and thrombus in one goat. The thrombus case was the longest surviving goat. The respiratory failure tended to occur when the extracorporeal circulation time was prolonged. Autotransfusion was effective for the prolongation of survival time. The left-right balance control and the suction control were performed successfully in all goats. The 1/R control was performed for a long time in five goats that survived for more than 1 month. With three goats that survived for 48, 52, and 53 days mainly with the pulsatile mode, the 1/R control was stable. With a goat that survived for 73 days, the nonpulsatile mode with the 1/R control could be tested for 3 weeks. With the longest surviving goat that was maintained mainly with the pulsatile mode, the 1/R control was unstable, possibly due to the mismatching of the response time of the control system between the computer and the body. However, liver and kidney functions were almost normal, and the total protein level recovered. Further study to stabilize the 1/R control in the UPTAH is necessary.


Evidence that the negative relationship between seed mass and relative growth rate is not physiological but linked to species identity: a within-family analysis of Scots pine.
Seed mass and relative growth rate (RGR) are important determinants of early seedling growth, and hence seedling establishment. Although a positive interspecific relationship between seed mass and seedling dry mass is well established, much less is known about the relationships among seed mass, seedling mass and RGR within species. We examined relationships among seed mass, seedling mass and RGR within and among maternal plant lines of Scots pine (Pinus sylvestris L.). To assess the effects of seed mass and maternal origin on RGR, individual seeds from two seed crops (years 2004 and 2005) of ten maternal plants growing under nursery conditions were weighed and then germinated. Seed mass was strongly determined by maternal plant, and seedling mass was largely determined by seed mass, with a positive correlation between these variables both across and within maternal plants. In contrast, RGR was weakly related to seed mass, with no consistent pattern in the sign of the relationship. It is well known that species differ in RGR and that RGR is related to seed mass across species. Lack of consistent evidence for this relationship within maternal lines, and for Scots pine overall, suggests that the relationship is not directly causal, but reflects consistent evolutionary covariation in these two physiologically independent traits.


Peptide-induced formation of cholesterol-rich domains.
The peptide N-acetyl-LWYIK-amide causes the reorganization of bilayers of phosphatidylcholine and cholesterol to produce domains enriched in cholesterol. At a cholesterol mol fraction of 0.5, addition of N-acetyl-LWYIK-amide results in the formation of cholesterol crystallites. Addition of this peptide to mixtures of 1-stearoyl-2-oleoylphosphatidylcholine with lower mol fractions of cholesterol results in an increase in the enthalpy of the chain melting transition of the phospholipid, indicating the depletion of cholesterol from a domain in the membrane. The peptide binds to membranes both with and without cholesterol. However, (1)H magic-angle spinning (MAS) nuclear Overhauser effect spectroscopy (NOESY) indicates that in the presence of cholesterol the peptide has greater penetration into the bilayer. (13)C MAS NMR indicates that the peptide has stronger interactions with the A ring of cholesterol than it does with the interior of the bilayer. These results are in contrast with those of another peptide, N-acetyl-KYWFYR-amide, which does not promote the formation of cholesterol crystallites and does not show preferential interaction with cholesterol by NMR. Therefore, cholesterol can promote the insertion of N-acetyl-LWYIK-amide into a membrane and this peptide will sequester cholesterol into domains. These properties help to explain the observation that this sequence is found to be important in causing the fusion protein of human immunodeficiency virus (HIV) to sequester into raft domains in biological membranes.


Phthalate exposures and human health concerns: A review and implications for practice.
High levels of exposure to phthalates have been associated with an increased risk for adverse male fetal reproductive development. Although animal studies have consistently demonstrated reproductive health effects, additional human epidemiological studies are needed to fully understand the potential harm to humans. Recent findings reported for humans have demonstrated endocrine-disrupting action similar to that associated with phthalate exposures in animals. As a result, phthalate exposure is an emerging public health concern that warrants further review. This article explores the state of the science on phthalate exposure, reviews the literature, and provides recommendations occupational health nurses can use to optimize the health of susceptible populations.


Social mobilization and political change in countries governed by the left: The cases of Argentina and Brazil.
This paper analyses the socio-political dynamics after the financial crash in two countries governed by the left, Argentina and Brazil. Whilst the economic crisis had an effect on the general distributive capacity of leftwing coalitions, it remains unclear why the political resolution of such a crisis adopted anti-regime features in Brazil and the form of an institutional alternation of power in Argentina. Our aim is to understand the new socio-political dynamics and their implications in the crisis of the left turn, especially the relationship between social mobilization and political change in the context of Argentina and Brazil. In doing so, the paper contributes to the growing body of literature interested in the intersections between social movements and the state. Based on the analysis of original qualitative and quantitative data on social protests events in both countries 2011-2015, the paper suggests that the complexity of changes in the socio-political dynamics can be captured by looking at three dimensions of the problem: grammar of mobilization, social imaginaries, and political representation. The main argument is that the different types of left turn strategy developed in both countries affected in turn the responses to the economic crisis and the new cycle of mobilization. The kirchnerist's movimentista strategy in Argentina contrasted with the demobilizing strategy of the PT in Brazil. Whilst the former contributed to channel the high and polarized levels of activism within the polity, the latter resulted in the crisis of the long cycle of political representation opened with the transition to democracy.


Diagnostic modeling of PAMS VOC observation.
Although a number of gas-phase chemical mechanisms, such as CBM-IV, RADM2, and SAPRC have been successful in studying gas-phase atmospheric chemical processes, they all used different combinations of lumped organic species to describe the role of organics in gas-phase chemical processes. Photochemical Assessment Monitoring Stations (PAMS) have been in use for over a decade and yet it is not clear how the detailed organic species measured by PAMS compare to the lumped modeled species. By developing a detailed mechanism specifically for the PAMS organics and embedding this diagnostic model within a regional-scale transport and chemistry model, one can then directly compare PAMS observation with regional-scale model simulations. By means of this comparison one can perhaps better evaluate model performance. The Taiwan Air Quality Model (TAQM) was modified by adding a submodel with transport processes and chemical mechanism for interactions of the 56 species observed by PAMS. It is assumed that TAQM can simulate the overall regional-scale environment including time evolution of oxidants and radicals; these results are then used to simulate the evolution of PAMS organics with species-specific source functions, meteorological transport, and chemical interactions. Model simulations of each PAMS organic were compared with PAMS hourly surface measurements. A case study with data collected at three sites in central Taiwan showed that when meteorological simulations were comparable with observations, diurnal patterns of most organics performed well with PAMS data after emissions were corrected. It is found emissions of over half of the PAMS species require correction, some by surprisingly large factors. With such correlation, simulated time evolution of ratios of ethylbenzene/m,p-xylenes and ethane/n-butane showed similar behaviors as shown by observation data. From the results of PAMS organics diurnal variations as well as indicator ratios, one can conclude that PAMS Air Quality Model (PAMS-AQM) has been successfully developed and can be applied to the study of evolution of PAMS organics in regional and urban environments. Further, one finds that an existing VOC emissions estimation procedure heavily dependent on U.S.-data based emissions speciation factors is suspect in application in Taiwan and perhaps in other countries as well. A protocol, using PAMS-AQM for testing consistency between detailed VOC emissions and PAMS observations, has been developed and demonstrated.


Cardiovascular toxicity and anxiety-like behavior induced by deltamethrin in zebrafish (Danio rerio) larvae.
Deltamethrin is widely used because of its low toxicity and high efficiency. Although its potential toxicity has been reported, its effects on cardiovascular system and motor behavior and its underlying mechanisms have remained unclear. In this study, the effects of deltamethrin on the development, cardiovascular system and motor behavior of zebrafish larvae and their possible mechanisms were evaluated using the transgenic zebrafish Tg (kdrl:mCherry) and Tg(myl7:GFP). At 72 hpf, the body length of larvae shortened, the head and eye area decreased, and the hatching rate increased. Acridine orange staining showed that treated zebrafish larvae produced different degrees of apoptosis in the head, body, heart and tail regions. Quantitative fluorescence intensity showed a dose-dependent increase in apoptosis signal, indicating that deltamethrin could induce apoptosis. Confocal images and fluorescence intensity quantification of red fluorescent protein-labeled vascular endothelial cell and green fluorescent protein-labeled transgenic zebrafish more clearly reflected the dose-dependent cardiac and vascular morphology and the damage caused by deltamethrin. Deltamethrin significantly induced vascular endothelial growth factor flk1 and fli-1, cardiac development-related gene myl7 decreased in a dose-dependent manner. In addition, deltamethrin increased the thigmotaxis of zebrafish larvae, causing anxiety-like behavior. Our study showed that deltamethrin could cause developmental toxicity, apoptosis, cardiovascular system damage and anxiety-like behavior, which provided a reference for the use of deltamethrin in agricultural production.


Ribosomal protein S6 from Xenopus laevis ovaries. Isolation, phosphorylation in vivo and cross-reaction with heterologous anti-S6 antibodies.
Ribosomal protein S6 from Xenopus laevis ovaries was prepared by ion-exchange chromatography on phosphocellulose and gel filtration on Sephadex G-75. The protein was identified as S6 from its position on two-dimensional polyacrylamide gels and from its immunological cross-reaction with monoclonal antibody raised against chicken liver S6, and from the fact that it is the major phosphorylated protein of the small subunit. When oocytes were incubated with [32P]orthophosphate in the presence of progesterone, 32P incorporation of 40-S ribosomal proteins was stimulated about 10-fold over controls without hormone. The bulk of the 32P radioactivity was incorporated into protein S6.


Eccentric loading for Achilles tendinopathy--strengthening or stretching?
The prescription of eccentric loading is considered as a mainstay of non-operative rehabilitation programmes for mid-substance chronic Achilles tendinopathy. Such exercises have some degree of clinical utility in comparison with concentric training and are often referred to as a strengthening programme. Yet the dose parameters of the eccentric loading do not reflect an optimal strengthening programme and specifically avoid the normal eccentric-concentric coupling typical of the stretch shortening cycle. This manuscript identifies the arguments and counterarguments for why eccentric loading rehabilitation is not an optimal strengthening programme. It is proposed that such exercises reflect a specific stretching programme directed at the passive structures. This has two important clinical implications. Firstly, this reinterpretation of the role of eccentric exercises may direct future research into the underlying mechanisms of tendinopathy and, secondly, it may reinforce the importance of adjunct sports specific strengthening programmes.


Development of a novel score (RENSAFE) to determine probability of acute kidney injury and renal functional decline post surgery: A multicenter analysis.
To create and validate 2 models called RENSAFE (RENalSAFEty) to predict postoperative acute kidney injury (AKI) and development of chronic kidney disease (CKD) stage 3b in patients undergoing partial (PN) or radical nephrectomy (RN) for kidney cancer. Primary objective was to develop a predictive model for AKI (reduction >25% of preoperative eGFR) and de novo CKD≥3b (<45 ml/min/1.73m2), through stepwise logistic regression. Secondary outcomes include elucidation of the relationship between AKI and de novo CKD≥3a (<60 ml/min/1.73m2). Accuracy was tested with receiver operator characteristic area under the curve (AUC). AKI occurred in 452/1,517 patients (29.8%) and CKD≥3b in 116/903 patients (12.8%). Logistic regression demonstrated male sex (OR = 1.3, P = 0.02), ASA score (OR = 1.3, P < 0.01), hypertension (OR = 1.6, P < 0.001), R.E.N.A.L. score (OR = 1.2, P < 0.001), preoperative eGFR<60 (OR = 1.8, P = 0.009), and RN (OR = 10.4, P < 0.0001) as predictors for AKI. Age (OR 1.0, P < 0.001), diabetes mellitus (OR 2.5, P < 0.001), preoperative eGFR <60 (OR 3.6, P < 0.001) and RN (OR 2.2, P < 0.01) were predictors for CKD≥3b. AUC for RENSAFE AKI was 0.80 and 0.76 for CKD≥3b. AKI was predictive for CKD≥3a (OR = 2.2, P < 0.001), but not CKD≥3b (P = 0.1). Using 21% threshold probability for AKI achieved sensitivity: 80.3%, specificity: 61.7% and negative predictive value (NPV): 88.1%. Using 8% cutoff for CKD≥3b achieved sensitivity: 75%, specificity: 65.7%, and NPV: 96%. RENSAFE models utilizing perioperative variables that can predict AKI and CKD may help guide shared decision making. Impact of postsurgical AKI was limited to less severe CKD (eGFR<60 ml/min 71.73m2). Confirmatory studies are requisite.


Recurrent patellar dislocation: reappraising our approach to surgery.
The management of recurrent traumatic patellar dislocation includes surgical realignment. There is no clear distinction whether proximal soft tissue or distal procedures produce superior results. However, distal realignment procedures are commonly associated with greater morbidity. We advocate a distal procedure only for cases which are more severe, such as the presence of patellar maltracking. Between January 2002 and June 2007, all patients who had a history of traumatic patellar dislocation with recurrent symptoms and failed conservative management underwent surgical realignment. Patients who had evidence of lateral patellar subluxation on computed tomography (CT) scan were offered a distal realignment procedure using the Elmslie-Trillat or Roux Goldthwaite procedure. All other patients underwent proximal soft tissue medial patellofemoral ligament (MPFL) reconstruction. Pre and postoperative functional International Knee Documentation Committee (IKDC), Lysholm and Tegner score assessments were performed for a minimum follow-up period of 6 months. The mean scores for each group were analysed using the Wilcoxon Matched-Pairs Signed-Ranks test and the Mann-Whitney U test was used to evaluate the difference between the groups. A total of 23 patients underwent surgery for patellar realignment. Of whom, 14 patients had a distal realignment procedure while 9 patients had a proximal procedure of MPFL reconstruction. There was greater morbidity reported with distal realignment procedures. Pre and postoperative IKDC, Lysholm and Tegner scores showed significant improvement for both treatment arms. However, there was no significant difference between the improvement scores for both groups. Patients with significant patellar maltracking following traumatic patellar dislocation would benefit from distal realignment using the Elmslie-Trillat or Roux Goldthwaite procedure. Otherwise, a proximal soft tissue procedure involving MPFL reconstruction would be adequate. A management algorithm is proposed for clinical use.


ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database.
Current pharmaceutical research and development (R&D) is a high-risk investment which is usually faced with some unexpected even disastrous failures in different stages of drug discovery. One main reason for R&D failures is the efficacy and safety deficiencies which are related largely to absorption, distribution, metabolism and excretion (ADME) properties and various toxicities (T). Therefore, rapid ADMET evaluation is urgently needed to minimize failures in the drug discovery process. Here, we developed a web-based platform called ADMETlab for systematic ADMET evaluation of chemicals based on a comprehensively collected ADMET database consisting of 288,967 entries. Four function modules in the platform enable users to conveniently perform six types of drug-likeness analysis (five rules and one prediction model), 31 ADMET endpoints prediction (basic property: 3, absorption: 6, distribution: 3, metabolism: 10, elimination: 2, toxicity: 7), systematic evaluation and database/similarity searching. We believe that this web platform will hopefully facilitate the drug discovery process by enabling early drug-likeness evaluation, rapid ADMET virtual screening or filtering and prioritization of chemical structures. The ADMETlab web platform is designed based on the Django framework in Python, and is freely accessible at http://admet.scbdd.com/ .


Confidence matters: a Self-Determination Theory study of factors determining engagement in self-management support practices of UK clinicians.
Within a national quality improvement programme for self-management of long-term conditions, we surveyed clinicians working with patients with diabetes, chronic obstructive pulmonary disease, musculoskeletal pain and depression. We applied the Self-Determination Theory framework to explore what factors can facilitate and impede the clinicians' engagement in clinical self-management support (SMS), patient centredness and organizational support for self-management. We also investigated whether attending professional training for clinicians in the practice of self-management (SM) increases motivation to support SM and reported use of SM practices. The study included 482 clinicians who were surveyed once (cross-sectional design) and 114 clinicians who were surveyed before and after training (longitudinal cohort). We found that the high level of satisfaction of competence need predicts practising SMS in all three areas (clinical SMS: beta coefficient = 0.21; p < 0.0001; patient centredness: beta coefficient = 0.50; p < 0.001; organizational SMS: coefficient = 0.20; p < 0.0001). Internalized regulation to support SMS increases engagement in clinical and organizational SMS. Upon comparing the two samples we explored the possible predictors of clinicians' self-referring to attend the training. Clinicians who volunteer to attend the training spend more time working directly with patients with long-term conditions (chi(2) = 4.8; df = 1; p = 0.02), had less previous relevant training (chi(2) = 4.77; df = 1; p = 0.02), and they have less autonomy to support SM (t = 5.0; df = 476; p < 0.0001). However, they report more engagement in patient-centred practices (t = 1.9; df = 585; p = 0.05). These factors are a good fit with the aims of the programme. We confirmed that attending the training had a significant, positive impact on clinicians' engagement in clinical SMS and patient centredness, as well as their overall confidence to support SM. We conclude that to facilitate clinicians to practice SMS it is very important to provide relevant professional training, professional support and incentives to foster clinicians' perceptions of their competence in relation to these practices. Organizations should develop a culture that values SMS, offer training to clinicians to enhance their sense of competence to effectively deliver SMS and support clinicians in finding their own way of supporting SM; in other words to create an optimal context to internalize regulation to support SM.


Atomoxetine versus placebo in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: a double-blind, randomized, multicenter trial in Germany.
The primary objective of this study was to evaluate the efficacy of atomoxetine (ATX, target dose 1.2 mg/kg daily) on symptoms of oppositional defiant disorder (ODD) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). A secondary objective was to compare fast versus slow up-titration of ATX. This was a 3-arm, 9-week, randomized, placebo-controlled, double-blind study in ADHD patients (6-17 years) with comorbid ODD (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] criteria A-C) or conduct disorder (CD). ATX-treatment arms were as follows-ATX-fast: 7 days 0.5 mg/kg, then 1.2 mg/kg; ATX-slow: 7 days each at 0.5 and 0.8 mg/kg, then 1.2 mg/kg. Primary outcome was the Swanson, Nolan, and Pelham Rating Scale-Revised (SNAP-IV) ODD-score after 9 weeks (Mixed Effects Model for Repeated Measures, ATX-up-titration groups pooled). In total, 181 patients were randomized, and 180 evaluated (ATX-fast/ATX-slow/placebo: 60/61/59). Baseline characteristics were comparable (84.4% boys; mean age 11.0 years; DSM-IV: 100% ADHD, 75.6% with combined type, 74.4% ODD, 24.4% CD; SNAP-IV ODD-scores, mean ± standard deviation 15.5 ± 4.35). At week 9, SNAP-IV ODD scores were significantly lower versus placebo in both ATX-groups (least square mean [95% confidence interval]: ATX-fast 8.6 [7.2;9.9]; ATX-slow 9.0 [7.7;10.3]; placebo 12.0 [10.6;13.5]; least square mean, ATX-pooled minus placebo: -3.2 [-5.0, -1.5], effect size: -0.69, p < 0.001). SNAP-IV ADHD-scores, CD symptoms (investigator-rated Attention-Deficit and Disruptive Behavior Disorders Instrument, disruptive behavior), Clinical Global Impressions-Severity, and individual treatment behaviors showed corresponding results. Post-hoc analyses indicated interrelationships between the medication effects on ADHD, ODD, and CD symptom scores. For ATX-slow, time to early dropout was significantly longer versus placebo (Hazard Ratio [95% confidence interval]: 3.57 [1.42;8.94]; p = 0.007). Clinically relevant adverse effects (fatigue, sleep disorders, nausea, and gastrointestinal complaints; weeks 1-3) were reported in 60.0% of ATX-fast, 44.3% of ATX-slow, and 18.6% of placebo group patients. ATX for 9 weeks significantly reduced symptoms of ODD/CD and ADHD; slower ATX-up-titration may be better tolerated.


Comparison of behavioral intervention and sensory-integration therapy in the treatment of challenging behavior.
The objective of the current study was to compare the effects of sensory-integration therapy (SIT) and a behavioral intervention on rates of challenging behavior (including self-injurious behavior) in four children diagnosed with Autism Spectrum Disorder. For each of the participants a functional assessment was conducted to identify the variables maintaining challenging behavior. Results of these assessments were used to design function-based behavioral interventions for each participant. Recommendations for the sensory-integration treatment were designed by an Occupational Therapist, trained in the use of sensory-integration theory and techniques. The sensory-integration techniques were not dependent on the results of the functional assessments. The study was conducted within an alternating treatments design, with initial baseline and final best treatment phase. For each participant, results demonstrated that the behavioral intervention was more effective than the sensory integration therapy in the treatment of challenging behavior. In the best treatment phase, the behavioral intervention alone was implemented and further reduction was observed in the rate of challenging behavior. Analysis of saliva samples revealed relatively low levels of cortisol and very little stress-responsivity across the SIT condition and the behavioral intervention condition, which may be related to the participants' capacity to perceive stress in terms of its social significance.


Recanalization of acute basilar artery occlusion improves outcomes: a meta-analysis.
Acute basilar artery occlusion (BAO) is a catastrophe with high mortality and disability. Randomized controlled trial (RCT) data supporting/refuting reperfusion treatment are sparse in acute BAO. The study objective was to pool risk estimates for death or dependency (DoD), mortality, and intracerebral hemorrhage (ICH) from published studies on BAO. Medline, Embase, The Cochrane Library, and clinicaltrials.gov were searched through August 2013 for studies of reperfusion therapies in acute BAO. Two independent authors selected studies and abstracted the data. Pooled risk ratios (RR) and mean weighted probabilities (MWP) were calculated using random effects model. 45 studies (n=2056) met the inclusion criteria. Recanalization was associated with a lower risk of DoD (RR 0.67; number needed to treat (NNT) 3) and mortality (RR 0.49; NNT 2.5). ICH rate (MWP) with acute therapies was 13%. With recanalization, RR for DoD in those treated ≤12 h was 0.63, and for those treated >12 h, it was 0.67. With recanalization, RR for DoD in the intravenous thrombolysis (IVT) subgroup was 0.68; in the intra-arterial/endovascular therapy (IA/EVT) subgroup, DoD RR was 0.67. Recanalization resulted in mortality RR of 0.46 in those treated ≤12 h; for >12 h group, RR was 0.50. Recanalization resulted in mortality RR of 0.53 in the IVT subgroup, and RR of 0.48 in the IA/EVT subgroup. ICH rate for ≤12 h was 10%; ICH rate for >12 h was 14%. With IVT, the ICH rate was 9%, and with IA/EVT the ICH rate was 14%. Recanalization of acute BAO leads to reduction in mortality by two-fold and reduction in the risk of DoD by 1.5-fold. This study underscores the equipoise in acute BAO for comparing systemic and endovascular therapies, and testing different time windows through RCTs.


Loss of K+ homeostasis in trout hepatocytes during chemical anoxia: a screening study for potential causes and mechanisms.
In isolated trout hepatocytes intoxication with CN- (chemical anoxia) leads to a rapid breakdown of K+ homeostasis. In the present study an attempt has been made to identify the causes and mechanisms underlying this phenomenon. Our results indicate that neither Ca2+ elevation nor cell swelling, both of which occurred during chemical anoxia and could be prevented by exposure to Ca2+ chelating agents or to hyperosmotic conditions, respectively, is solely responsible for the breakdown of K+ homeostasis. From a number of inhibitors of dissipative K+ fluxes tested, only BaCl2, an inhibitor of voltage-gated K+ channels, proved to be effective in significantly reducing K+ efflux during chemical anoxia. The KCl cotransporter known to be involved in regulatory volume decrease after hypoosmotic shock does not seem to be activated during CN(-)-induced cell swelling.


Plasma triglyceride as a risk factor for cardiovascular disease.
To determine whether cardiovascular disease can be predicted from plasma triglyceride levels independent of high density lipoprotein (HDL) cholesterol levels. Seventeen prospective population-based studies, ranging in publication date from 1965 to 1994, were selected based on uniform criteria. Among the studies, 16 were conducted in men, comprising data for more than 46,000 men, with an average follow-up period of more than eight years. The data from women came from five studies, including nearly 11,000 women with an 11-year average follow-up. The meta-analysis protocol comprised the following steps: estimating the relative risk of triglyceride for each individual study; standardizing the relative risks to a 1 mmol/l increase; estimating the variance and weighting relative risks by the inverse of the variance, and estimating the summary relative risk by averaging the weighted relative risks. Among studies of men, relative risks ranged from 1.1 to 2.0, and the summary relative risk was 1.32 (P < 0.05). All five studies of women were statistically significant, with relative risks ranging from 1.7 to 2.0. The summary relative risk was 1.76, higher than that for men, indicating a 76% increase in risk for women. For the studies among men in which HDL cholesterol data were available, multivariate adjusted relative risk was attenuated to 1.14 but was still statistically significant. Although only two studies of women included HDL cholesterol adjustments, the summary relative risk for triglyceride remained statistically significant, with a value of 1.37. When all available data are taken into account, increased triglyceride level is a risk factor for cardiovascular disease, independent of HDL cholesterol level. Clinical trials are urgently needed to determine whether lowering plasma triglyceride levels reduces subsequent risk of cardiovascular disease.


Nonshivering thermogenesis in king penguin chicks. I. Role of skeletal muscle.
In cold-acclimatized (CA) king penguin chicks exhibiting nonshivering thermogenesis (NST), protein content and cytochrome oxidase (CO) activity of tissue homogenates were measured together with protein content, CO, and respiration rates of isolated mitochondria from skeletal muscle (gastrocnemius and pectoralis) and liver. The comparison was made with chicks reared at thermoneutrality (TN) for at least 3 wk. In CA chicks showing a NST despite the lack of brown adipose tissue, an increase in thermogenic capacity was observed in skeletal muscle in which the oxidative capacity rose (+28% and +50% in gastrocnemius and pectoralis muscles, respectively), whereas no change occurred in the liver. Oxidative capacity of skeletal muscle increased together with the development of mitochondrial inner membrane plus cristae in muscles of CA chicks contrary to their TN littermates (+30 to +50%). Subsarcolemmal mitochondria of CA chicks had a higher protein content (+65% in gastrocnemius muscle) and higher oxidative capacities than in controls. The lower respiratory control ratio of these mitochondria might result from a low ADP phosphorylation rate. No change occurred in the intermyofibrillar fraction nor in liver mitochondria. These findings together with earlier results obtained in cold-acclimated ducklings indicate the marked and suited adaptation of skeletal muscle and in particular of subsarcolemmal mitochondria allowing them to play a role in NST.


Left ventricular performance in coronary artery disease evaluated with systolic time intervals and echocardiography.
Simultaneous determinations of systolic time intervals (preejection period index [PEPI], left ventricular ejection time index [LVETI] and ratio of preejection period to left ventricular ejection time [PEP/LVET]) and echographic measures of left ventricular performance (percent change in minor axis diameter [%delta D], circumferential shortening rate [Vcf] and end-diastolic diameter [Dd]) were obtained in 25 normal subjects and 37 patients with previously documented transmural myocardial infarction. The group with previous infarction demonstrated significant (P less than 0.001) differences from the normal group in each of the noninvasive measures. PEP/LVET and %deltaD were the most sensitive measures of left ventricular dysfunction. Deviation from the normal range in these measures occurred, respectively, in 70 and 65 percent of patients without dyspnea or fatigability (20 patients) and 85 percent of those without angina pectoris (13 patients). Abnormalities in systolic time interval and echocardiographic measures were related to the severity of dyspnea and fatigability but not to that of angina. Neither the presence of phonocardiographically documented third or fourth sound gallops nor an abnormal cardiothoracic ratio by chest roentgenogram reliably detected patients with abnormal left ventricular performance. The range of abnormality in left ventricular performance did not differ between patients with prior anterior or diaphragmatic myocardial infarction. The frequency of abnormal performance was greatest among patients with combined sites of prior infarction. Among 26 patients studied by coronary arteriography, abnormal left ventricular performance as determined by values for PEP/LVET and %deltaD occurred in fewer than 30 percent of those with 70 percent or greater obstruction of one coronary artery and in more than 80 percent of those with two or three vessel involvement. There was a high correlation between systolic time intervals, %delta D and Vcf, the closest correlation occurring between PEP/LVET and %deltaD (r = -0.93). These data document the sensitivity of the noninvasive systolic time intervals and echographic measures and their superiority over current clinical bedside methods in evaluating left ventricular performance in patients with prior myocardial infarction.


An examination of dyadic changes in optimism and physical health over time.
Having a partner high in optimism is associated with better health in older adults. However, partners, just like individuals, are not static entities and likely change considerably over time. The current study examined whether changes in one person's optimism was associated with corresponding changes in his or her partner's health over a 4-year period. We employed a sample of 2,758 heterosexual couples (5,516 individuals; Mage = 65.81, SD = 9.00), married an average of 36.06 years. Median level of education was at least a high school education (13.0% had less than a high school education; 56.1% had a high school education; 30.9% had at least some college education). Both couple members filled out measures of optimism and health twice over a 4-year period. Having a partner high in optimism at baseline was associated with increases in an actor's optimism 4 years later, r = .08, p < .001. Baseline self-rated health and chronic illness of actors and their partners were mostly unrelated to changes in optimism. However, actor (rs > .05) and partner (rs > .03) changes in optimism were associated with changes in self-rated health and chronic illnesses over time. There was also some evidence for an interaction effect (rs > .03), such that the worst outcomes were experienced among couples in which both members decreased in optimism. This is the first study to examine how changes in psychological characteristics are associated with changes in health within and across romantic partners. Possible mechanisms are discussed. (PsycINFO Database Record


Scipion-Chem: An Open Platform for Virtual Drug Screening.
Virtual drug screening (VDS) tackles the problem of drug discovery by computationally reducing the number of potential pharmacological molecules that need to be tested experimentally to find a new drug. To do so, several approaches have been developed through the years, typically focusing on either the physicochemical characteristics of the receptor structure (structure-based virtual screening) or those of the potential ligands (ligand-based virtual screening). Scipion is a workflow engine well suited for structural studies of biological macromolecules. Here, we present Scipion-chem, a new branch oriented to VDS. A total of 11 plugins have already been integrated from the most common programs used in the field. They can be used through the Scipion graphical user interface to execute and analyze typical VDS tasks. In addition, we have developed several consensus protocols that combine results from the different integrated programs to generate more robust predictions. Backstage, Scipion also facilitates the interoperability of those different software packages while tracking all of the intermediate files, parameters, and user decisions. In summary, in this article, we present Scipion-chem. This accessible, interoperable, and traceable platform provides the user with all of the tools to carry out a successful VDS workflow. Scipion-chem is openly available at https://github.com/scipion-chem.


Clinical significance of serum protease-activated receptor-1 levels in gastric cancer patients.
Protease-activated receptor-1 (PAR-1) has a significant role in the pathogenesis of various malignancies and its expression mainly affects the survivals of cancer patients. The aim of the present study was to determine the clinical significance of the serum concentrations of PAR-1 in patients with gastric carcinoma. A total of 63 pathologically confirmed gastric cancer patients were enrolled in this study, with a median age of 62 years. Serum PAR-1 concentrations were determined by the enzyme-linked immunosorbent assay method and no significant difference in the baseline serum PAR-1 concentrations was found between patients and normal controls (P=0.5). The investigated clinical variables, including patient age, gender, localization of lesion, histology, grade of pathology, disease stage and serum tumor markers (lactate dehydrogenase, carcinoembryonic antigen and carbohydrate antigen 19-9) were not correlated with serum PAR-1 levels (P>0.05). Furthermore, no association was identified between the serum PAR-1 level and chemotherapy responsiveness (P=0.43). Serum PAR-1 level also had no prognostic role for survival (P=0.27). In conclusion, the serum PAR-1 concentration has no diagnostic, predictive and prognostic values in gastric cancer patients.


Exploring the sensitivity of the Personality Assessment Inventory symptom validity tests in detecting response bias in a mixed neuropsychological outpatient sample.
Few studies have evaluated the symptom validity tests (SVTs) within the Personality Assessment Inventory (PAI) in a neuropsychological assessment context. Accordingly, the present study explored the accuracy of PAI SVTs in identifying exaggerated cognitive dysfunction in a mixed sample of outpatients referred for neuropsychological assessment. Participants who failed two or more Performance Validity Tests (PVTs) were classified as having exaggerated cognitive dysfunction (n = 49). Their responses on PAI SVTs were compared to examinees who did not fail PVTs (n = 257). Multivariate analysis of variance indicated the Negative Impression Management (NIM) scale most strongly discriminated between those with exaggerated cognitive dysfunction from honest responders (Cohen's d = .58). Nonetheless, its classification accuracy was low (area under the curve [AUC] = .65). A k-means cluster analysis and a subsequent multinomial logistic regression indicated evidence for two distinct groups of exaggerators. In particular, one group seemed to exaggerate symptoms, whereas another presented in a defensive manner, implying that individuals with positive and NIM biases on the PAI were apt to display invalid performance on PVTs. Findings indicated that exaggerated cognitive dysfunction tends to be present when NIM is very high and that evidence exists for a defensive response style on the PAI in the context of PVT failure.


Observations on the production of pyrogenic substances by rabbit and human leucocytes.
1. The mechanism of release of a pyrogen from leucocytes has been studied in cells obtained from sterile rabbit peritoneal exudates and from rabbit blood. Attempts were made to induce human leucocytes-from blood-to release a pyrogen. 2. Rabbit leucocytes, kept below 4 degrees C., were not pyrogenic and did not release any pyrogen when disintegrated. Incubating such cells, in various media, at 37 degrees C. led to the formation of a pyrogen which was heat-labile. The maximum yield was attained after 1(1/2) hours' incubation. 3. The formation of rabbit leucocytic pyrogen was prevented by freezing and thawing the leucocytes, by heating them to 56 degrees C. for half an hour before incubation, and by ageing them in the cold. 4. Nitrofurazone (5-nitro-2-furaldehyde semicarbazone) prevents the formation of leucocytic pyrogen when given by mouth to the cell-donor animals, or when added to leucocytes in intro. 5. Leucocytes from rabbit blood formed leucocytic pyrogen, on incubation in saline, and this formation was also inhibited by nitrofurazone. 6. No leucocytic pyrogen was released from human leucocytes subjected to mechanical, osmotic, or thermal damage, and it was not formed when the cells were incubated in saline. 7. The source of rabbit leucocytic pyrogen, the action of nitrofurazone on leucocytes, and the supposed role of leucocytic pyrogen in fever are discussed.


Measures for low back pain: a proposal for clinical use.
Low back pain represents a serious public health problem. Therefore, great efforts have been made in order to improve and assess the efficacy of its treatment. Reports in international literature have presented important studies concerning instruments to assess pain and functional incapacity in patients with low back pain. This study presents a clinical protocol which was developed by a multidisciplinary team. This protocol consists of the evaluation and distribution of pain, The Spitzer Quality of Life, The Oswestry Low Back Pain Disability Questionnaire, and The Center for Epidemiological Studies Depression Scale. Instruments must be urgently developed or adapted in order to be used according to the Brazilian reality.


Conformational space and photochemistry of alpha-terpinene.
Alpha-terpinene is a natural product that is isolated from a variety of plant sources and is used in the pharmaceutical and perfume industries. In the atmosphere, under the influence of sunlight, alpha-terpinene undergoes a series of photochemical transformations and contributes to the formation of the secondary organic aerosols. In the present work, alpha-terpinene has been isolated in low-temperature xenon and argon matrices, and its structure and photochemistry were characterized with the aid of FTIR spectroscopy and DFT calculations. The theory predicts three conformers resulting from the rotation of the exocyclic CH(CH(3))(2) framework, that is, Trans (T) and Gauche (G+ and G-) forms. The two Gauche conformers were estimated to be higher in energy, by ca. 1.75 kJ mol(-1), than the most stable Trans form. The signatures of all three conformers were found to be present in the experimental low-temperature matrix spectra with the T form dominating in diluted matrices. The conformational ratio was found to shift in favor of the G+/G- forms upon annealing of the matrices as well as in the neat alpha-terpinene liquid. UV-C (lambda > 235 nm) irradiation of matrix-isolated alpha-terpinene led to its isomerization into an open-ring species, which is produced in the Z configuration and in the conformations that require the smallest structural rearrangements of both the reagent and matrix.


Rotated split palatal flap for soft tissue primary coverage over extraction sites with immediate implant placement. Description of the surgical procedure and clinical results.
Immediate implant placement after tooth extraction is becoming a common procedure in implant-supported oral rehabilitation. However, lack of primary full flap closure can jeopardize final results. A surgical approach that would enable predictable primary soft tissue closure over implants placed into fresh extraction sockets is described and evaluated. This technique is based on a rotated deep split thickness palatal flap (RSPF) containing periosteum and connective tissue, covering the implant and/or a barrier membrane. In 29 patients, 33 consecutive implants were placed immediately post extraction of 1 or 2 anterior or premolar maxillary teeth. Patients were divided in 2 groups: Group A (15 patients; n = 18 sites) where no barrier membrane was used and Group B (14 patients, n = 15 sites) where an occlusive resorbable collagen membrane was used. Distance between the alveolar crestal bone and the coronal aspect of the implant was measured at time of implant placement (Group A: mean 1.9 mm, SD 1.16; Group B: mean 4.6 mm, SD 1.18) and at second stage surgery (Group A: mean 0.3 mm, SD 0.46; Group B: mean 0. 7 mm, SD 0. 7). The difference between both records (crestal bone formation) was calculated (Group A: 1.7 mm, SD 1.03; Group B: 3.9 mm, SD 1.12) and found to be statistically significant (P <0.0001). Crestal bone formation, relative to the initial bone crest-implant distance at time of implant placement was approximately 85% in both groups. In 4 sites (2 in each group), where the cover screws were exposed before second stage surgery, complete crestal bone regeneration did not occur. Use of a barrier membrane may be obviated in appropriate cases while placing implants into fresh extraction sites. This procedure offers a predictable treatment approach in achieving complete soft tissue coverage, while allowing for healing of bony defects in immediate implantation procedures.


The capacity and resolution of spatial working memory and its role in the storage of non-spatial features.
The question whether the storage of spatial locations and other non-spatial features in visual working memory (WM) is based on shared or separate processes remains unresolved. We recorded contralateral delay activity (CDA) components as on-line electrophysiological markers of WM maintenance in two tasks where observers had to retain either the colors or locations of sample stimuli. CDA components were elicited both in the Color and in the Location task, and increasing WM load had identical effects on CDA amplitudes, suggesting shared underlying mechanisms. However, CDA amplitudes were generally larger in the Location Task. Experiment 2 demonstrated that the CDA is sensitive to the resolution demands of spatial WM tasks. CDA amplitudes elicited during the storage of object locations in WM were larger when these locations had to be retained with higher precision. These findings support the hypothesis that spatial and non-spatial features of visual objects are represented in an integrated fashion in WM. The activation of these representations is controlled by space-based attentional control processes, and their spatial resolution can be regulated in line with current task demands.


Home-delivered problem adaptation therapy (PATH) for depressed, cognitively impaired, disabled elders: A preliminary study.
This preliminary study examines the efficacy of 12-week home-delivered problem adaptation therapy (PATH) versus home-delivered supportive therapy (ST) in reducing depression and disability in 30 depressed, cognitively impaired, disabled older adults. A 12-week randomized clinical trial. Research assistants were unaware of the participants' randomization status. Assessments were conducted at baseline, 6 weeks, and 12 weeks. Weill-Cornell Advanced Center for Interventions and Services Research. Thirty elders with major depression, cognitive impairment, and disability were recruited through advertisement and the Home-Delivered Meals Program of the Westchester County Department of Senior Programs and Services. PATH is a home-delivered intervention designed to reduce depression and disability in depressed, cognitively impaired, disabled elders. PATH is based on problem-solving therapy and integrates environmental adaptation and caregiver participation. PATH is consistent with Lawton's ecologic model of adaptive functioning in aging. Depression and disability were measured with Hamilton Depression Rating Scale-24 items and Sheehan Disability Scale, respectively. Client Satisfaction Questionnaire was used to assess patient satisfaction with treatment. Mixed-effects model analyses revealed that PATH was more efficacious than ST in reducing depression and disability at 12 weeks. Participants in both treatment groups were satisfied with treatment. This preliminary study suggests that PATH is well accepted and efficacious in depressed elders with major depression, cognitive impairment, and disability. Because this population may not adequately respond to antidepressant medication treatment, PATH may provide relief to many patients who would otherwise remain depressed and continue to suffer.


Microvessel density and vascular endothelial growth factor expression as predictors of childrens' survival from cerebellar medulloblastoma.
Cerebellar medulloblastoma is the most common malignant brain tumor of childhood. This neoplasm is highly vascular and has a high growth rate. We aimed to determine whether high microvessel density (MVD) and expression of vascular endothelial growth factor (VEGF) in medulloblastoma tissue is correlated with survival time in children with this tumor. Tissue from 32 cerebellar medulloblastomas in 14 girls and 18 boys was studied. The standard-risk group comprised patients older than 3 years, without metastases of medulloblastoma and a residual post-operative tumor with a surface area less than 1.5 cm(2). The patients assigned to a high-risk group had at least one of the following indicators: younger than 3 years, metastases, or a residual post-operative tumor with a surface area larger than 1.5 cm(2). For each tumor, MVD was determined and the expression of VEGF was assessed using immunohistochemical techniques. The 5-year survival rate for the 32 patients was 56.2%. Five-year survival rates were 70.6% and 40.0% for patients in the standard-risk and high-risk groups, respectively. The mean (+/-standard deviation, SD) MVD for all patients was 22.0+/-9.1 microvessels per 0.7 mm(2). There was no difference in the survival rate between the groups with above-average MVD and below-average MVD (66.7% and 50.0%, respectively). Testing revealed 7 tumors with VEGF expression and 25 without. The 5-year survival rates for these 2 groups were not significantly different (57.1% vs. 56.0%, respectively). The mean (+/-SD) MVD values for the VEGF-positive and VEGF-negative groups were not significantly different (19.1+/-6.5 vs. 22.9+/-9.7 microvessels per 0.7 mm(2), respectively, Mann-Whitney U-test=78.5, Z=-0.41, p=0.68). There were no significant correlations between risk groups and expression of VEGF or MVD. These results indicate that neither high MVD nor the expression of VEGF in tumor tissue predicts poor prognosis in children with cerebellar medulloblastoma.


Weekly iron supplementation does not block increases in serum zinc due to weekly zinc supplementation in Bangladeshi infants.
Because infants and young children in many developing countries are deficient in both iron and zinc, and zinc can affect iron metabolism, evaluation of optimum strategies to simultaneously supplement iron and zinc is an important public health priority. This study evaluated the efficacy of weekly supplementation of iron or zinc or both on iron, zinc, and copper status in Bangladeshi infants. In a double-blind, randomized, controlled community trial, 6-mo-old infants were assigned to receive weekly supplements of 1 mg riboflavin (control, n = 82) or 1 mg riboflavin + 20 mg iron (n = 83), 20 mg zinc (n = 83), or both (n = 85) for 6 mo. Hemoglobin, serum ferritin, transferrin receptor, zinc, and copper concentrations were measured at baseline and at the end of intervention. Serum Zn increased in both groups receiving zinc; the increase was greatest among children with low baseline serum zinc concentration. Iron status indicators did not differ among the groups before or after 6 mo of supplementation. Supplementation with either zinc or iron decreased serum copper after 6 mo. Joint supplementation did not alter the individual effects of iron or zinc supplementation in these Bangladeshi children. However, the dosing regimen may not have been adequate to achieve the desired biochemical effects.


Parent use of touchscreen computer kiosks for child health promotion in community settings.
The goals were to evaluate the use of touchscreen computer kiosks, containing only child health-promoting information, in urban, low-income, community settings and to characterize the users of these kiosks. Three user-driven touchscreen computer kiosks were placed in low-income urban locations in Seattle, Washington, from March 2005 to October 2005. The locations included a public library, a Department of Motor Vehicles office, and a McDonald's restaurant. Users selected age-appropriate modules with prevention information and screening tools. Users entered the age of the child and were presented with age-appropriate modules. On exiting, users were asked to rate their experience and to provide basic demographic data. In total, there were 1846 kiosk sessions. Almost one half occurred at McDonald's. Seventy-eight percent of users identified themselves as first-time users. Users sought information for children of all ages. Sixty-one percent of first-time users explored 1 module. First-time users were most interested in television/media use (16%), smoke exposure (14%), attention-deficit/hyperactivity disorder screening (12%), and asthma assessment (11%). At-risk children were identified in 52% of sessions. Eighty-seven percent of first-time users who completed the asthma assessment had children whose asthma was uncontrolled. Twenty-eight percent of users responded to > or = 1 question on the exit survey. Of those, 48% had less than a high school education, and 26% had never used the Internet. Approximately one half found the kiosk easy to use (57%) and the information easy to understand (55%); 66% said there was at least some new information. Fifty-five percent planned to try some of the things they had learned, and 49% intended to talk to their child's doctor about what they had learned. User-driven computer kiosks were used in community settings to obtain child health information. Users found the kiosks easy to use. Additional study on improving use and understanding the impact is needed.


Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group.
To compare three-drug chemotherapy with cisplatin, doxorubicin, and methotrexate with four-drug chemotherapy with cisplatin, doxorubicin, methotrexate, and ifosfamide for the treatment of osteosarcoma. To determine whether the addition of muramyl tripeptide (MTP) to chemotherapy enhances event-free survival (EFS) and overall survival in newly diagnosed patients with osteosarcoma. Six hundred sixty-two patients with osteosarcoma without clinically detectable metastatic disease and whose disease was considered resectable received one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 x 2 factorial design. The primary end points for analysis were EFS and overall survival. In the current analysis, there was no evidence of interaction, and we were able to examine each intervention separately. The chemotherapy regimens resulted in similar EFS and overall survival. There was a trend toward better EFS with the addition of MTP (P = .08). The addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P = .03). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI, 0.52 to 0.96). The addition of ifosfamide to cisplatin, doxorubicin, and methotrexate did not enhance EFS or overall survival for patients with osteosarcoma. The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.


TA repeat polymorphism of the 5alpha-reductase gene and breast cancer.
There is increasing evidence that androgens play a significant role in the development and progression of breast cancer. 5alpha-Reductase (SRD5A2) is an enzyme that is expressed in androgen-dependent tissues, and it catalyzes the reduction of testosterone to its more bioactive form, dihydrotestosterone, which then transactivates a number of genes. One of these genes encodes for prostate-specific antigen (PSA), a favorable prognostic factor in breast cancer. The 3' untranslated region of the SRD5A2 gene contains either no TA repeats [(TA)0] or 9 [(TA)9] or 18 [(TA)18] repeats. Variations in the length of these dinucleotide repeats have been reported to influence the enzymatic activity of SRD5A2. In this study, we determined the TA genotypes in DNA from 141 well-characterized breast tumors and in DNA from whole blood of 70 women without cancer. The presence of TA genotypes was then associated with tumor cytosolic PSA concentrations and with clinicopathological variables, including disease-free survival and overall survival. Three genotypes, (TA)0 homozygote, (TA)0/(TA)9 heterozygote, and (TA)9 homozygote, were identified. No (TA)18 alleles were detected in any of the two patient groups. A statistically significant association between high PSA concentrations and (TA)0/(TA)9 or (TA)9 genotypes was observed (P = 0.004). (TA)0/(TA)9 or (TA)9 genotypes were found less frequently in patients at stage III or IV disease. TA genotypes were not associated with other clinicopathological variables by contingency table analysis. Patients with (TA)0/(TA)9 or (TA)9 repeats, when compared to those with genotypes homozygous for the (TA)0 allele, showed a significant reduction in the risk for relapse (P = 0.043). Long-term studies are needed to investigate the relevance of this polymorphism to breast cancer susceptibility.


Strength and precision of neurotransmission at mammalian presynaptic terminals.
Classically, the basic concept of chemical synaptic transmission was established at the frog neuromuscular junction, and direct intracellular recordings from presynaptic terminals at the squid giant presynaptic terminal have further clarified principles of neurotransmitter release. More recently, whole-cell patch-camp recordings from the calyx of Held in rodent brainstem slices have extended the classical concept to mammalian synapses providing new insights into the mechanisms underlying strength and precision of neurotransmission and developmental changes therein. This review summarizes findings from our laboratory and others on these subjects, mainly at the calyx of Held, with a particular focus on precise, high-fidelity, fast neurotransmission. The mechanisms by which presynaptic terminals acquire strong, precise neurotransmission during postnatal development are also discussed.


Programming PAM antennae for efficient CRISPR-Cas9 DNA editing.
Bacterial CRISPR-Cas9 nucleases have been repurposed as powerful genome editing tools. Whereas engineering guide RNAs or Cas nucleases have proven to improve the efficiency of CRISPR editing, modulation of protospacer-adjacent motif (PAM), indispensable for CRISPR, has been less explored. Here, we develop a DNA origami-based platform to program a PAM antenna microenvironment and address its performance at the single-molecule level with submolecular resolution. To mimic spatially controlled in vivo PAM distribution as may occur in chromatin, we investigate the effect of PAM antennae surrounding target DNA. We find that PAM antennae effectively sensitize the DNA cleavage by recruiting Cas9 molecules. Super-resolution tracking of single single-guide RNA/Cas9s reveals localized translocation of Cas9 among spatially proximal PAMs. We find that the introduction of the PAM antennae effectively modulates the microenvironment for enhanced target cleavage (up to ~50%). These results provide insight into factors that promote more efficient genome editing.


Allometry of facial mobility in anthropoid primates: implications for the evolution of facial expression.
Body size may be an important factor influencing the evolution of facial expression in anthropoid primates due to allometric constraints on the perception of facial movements. Given this hypothesis, I tested the prediction that observed facial mobility is positively correlated with body size in a comparative sample of nonhuman anthropoids. Facial mobility, or the variety of facial movements a species can produce, was estimated using a novel application of the Facial Action Coding System (FACS). I used FACS to estimate facial mobility in 12 nonhuman anthropoid species, based on video recordings of facial activity in zoo animals. Body mass data were taken from the literature. I used phylogenetic generalized least squares (PGLS) to perform a multiple regression analysis with facial mobility as the dependent variable and two independent variables: log body mass and dummy-coded infraorder. Together, body mass and infraorder explain 92% of the variance in facial mobility. However, the partial effect of body mass is much stronger than for infraorder. The results of my study suggest that allometry is an important constraint on the evolution of facial mobility, which may limit the complexity of facial expression in smaller species. More work is needed to clarify the perceptual bases of this allometric pattern.


Intracranial angioplasty and/or stent placement in octogenarians is associated with a threefold greater risk of periprocedural stroke or death.
To compare the clinical and angiographic outcomes of endovascular treatment of symptomatic intracranial stenosis between octogenarian and younger patients. Data for 244 consecutive patients (173 men; mean age 61.6 years) who underwent angioplasty and/or stenting for intracranial atherosclerotic disease at 5 specialized centers were pooled. Baseline, 30-day, and follow-up clinical and angiographic information were collected. Rates of clinical and angiographic endpoints were compared between patients >or=80 years old versus those <80 years. Patients >or=80 years (n = 15) were more likely to be hypertensive (87% versus 69%) and have underlying coronary artery disease (73% versus 36%, p<0.05) compared to younger patients (n = 229). The rate of periprocedural stroke and/or death was 3-fold higher among patients aged >or=80 years compared with those <80 years (20% versus 7%, p = 0.11). No recurrent stroke or death (excluding periprocedural events) was observed during follow-up in the octogenarian group. In patients who had follow-up angiography, a similar rate of >or=50% restenosis was observed among patients aged >or=80 years and those aged <80 years (25% versus 29%, p>0.1). The 3-fold higher periprocedural death and/or stroke rate suggests cautious use of intracranial angioplasty and/or stent placement in octogenarians.


Timing of maternal exposure to a high fat diet and development of obesity and hyperinsulinemia in male rat offspring: same metabolic phenotype, different developmental pathways?
Objective. Offspring born to mothers either fed an obesogenic diet throughout their life or restricted to pregnancy and lactation demonstrate obesity, hyperinsulinemia, and hyperleptinemia, irrespective of their postweaning diet. We examined whether timing of a maternal obesogenic diet results in differential regulation of pancreatic adipoinsular and inflammatory signaling pathways in offspring. Methods. Female Wistar rats were randomized into 3 groups: (1) control (CONT): fed a control diet preconceptionally and during pregnancy and lactation; (2) maternal high fat (MHF): fed an HF diet throughout their life and during pregnancy and lactation; (3) pregnancy and lactation HF (PLHF): fed a control diet throughout life until mating, then HF diet during pregnancy and lactation. Male offspring were fed the control diet postweaning. Plasma and pancreatic tissue were collected, and mRNA concentrations of key factors regulating adipoinsular axis signaling were determined. Results. MHF and PLHF offspring exhibited increased adiposity and were hyperinsulinemic and hyperleptinemic compared to CONT. Despite a similar anthropometric phenotype, MHF and PLHF offspring exhibited distinctly different expression for key pancreatic genes, dependent upon maternal preconceptional nutritional background. Conclusions. These data suggest that despite using differential signaling pathways, obesity in offspring may be an adaptive outcome of early life exposure to HF during critical developmental windows.


Perinatal outcomes following mid trimester detection of isolated short foetal femur length.
Short foetal femur length (FL) is a normal variant but may also be a marker for disorders such as skeletal dysplasia, Trisomy 21 (T21), Turners syndrome, congenital infection (TORCH) and foetal growth restriction (FGR). Our aim was to review outcomes in our population following a diagnosis of isolated short FL (FL <5th centile) when detected at the time of mid trimester foetal anomaly scan (FAS). All women within NHS Tayside who attended for routine mid trimester foetal anomaly scan at 18-21 weeks gestation (Range = 18+2-21+3 weeks) between November 2011 and June 2016 were included. Those who had an isolated FL <5th centile were identified using Viewpoint. Data relating to perinatal and childhood outcomes were obtained from local databases. 72 women were identified. The median maternal age was 30 years (range = 17-45 years). 39/72 (54.2%) women were primigravid. 41/72 (56.9%) women had Down's syndrome screening (DSS). 12/72 (16.7%) women were offered TORCH screens, none of which were positive for recent or current infection. Invasive testing was performed in 8/72 (11%) women; 1 had previously had first trimester chorionic villus sampling (CVS) for raised maternal age. 7 women had amniocentesis (1 prior to FAS for increased DSS risk). All those that had invasive testing had normal foetal karyotype. Median gestational age at delivery was 38 weeks (range = 26-41 weeks). 10/72 (13.9%) had genetic testing after birth, 6 were performed shortly after birth due to dysmorphic features. 4/72 (5.5%) had Trisomy 21 and 3 of these had VSD that had not been identified antenatally. For those with T21, 3 mothers had declined DSS and 1 had a low risk DSS result. Fifty out of seventy two (69.4%) babies had constitutionally short femurs. 13/72 (18%) had FGR and 3/72 (4.2%) had skeletal dysplasia. One baby had William's syndrome, one had Klinefelter syndrome and two had genetic deletions of uncertain significance. Knowledge of outcomes will enable better counselling for women with isolated short foetal femur. In our local population, more than two-thirds of the babies with isolated short femur will be normal. Women must, however, be informed of the potential for foetal aneuploidy and foetal skeletal dysplasia. In view of this, women should be offered invasive testing and follow-up ultrasound scans to assess the foetal skeleton. Furthermore isolated short foetal femur is a marker for FGR and all women with isolated short femur should be offered serial ultrasound scans to assess foetal growth and well-being in the third trimester.


[The demonstration of steady-state Ca2+ influx into the cells of the salivary glands in Chironomus plumosus L. larvae and its role in basal secretion].
Ca2+ content in Chironomus plumosus salivary gland tissue we determined using Ca(2+)-sensitive dye arsenazo III and protein concentration in medium--by Lowry method. It was showed correlation between increasing of Ca2+ content in gland and basal secretion. So, basal secretion is Ca(2+)-dependent process. Owing to adding to medium verapamil, diltiazem and nifedipine (10(-4) M) took place decreasing of Ca2+ content and secretion. Since decreasing of Ca2+ entry in cells owing to blocators action did't exceed 53% (in the case of nifedipine) we assumed that permanent Ca2+ entry formed by potential- and receptor-operated channels. It was established dependence of continuous Ca2+ entry in cells, basal secretion and effectiveness of blockade of Ca(2+)-channels by nifedipine on the [Ca2+]e. Therefore, through the exocrine secretory cells membrane of Chironomus plumosus larvae salivary gland carry out continuous diffuse Ca2+ entry for maintain of basal secretion by cells. This Ca2+ entry provide by population of open Ca(2+)-channels, sensitive to blocators of potential dependent of Ca(2+)-conduction plasmatic membrane.


Medical care of pregnant women with type 1 diabetes: current guidelines and clinical practice.
The prevalence of all types of diabetes mellitus is increasing worldwide. Diabetes is a common metabolic complication of pregnancy. For many years, pregnancy complicated by type 1 diabetes was associated with a particularly poor prognosis, and while this has changed dramatically over the last 2 decades, a lot has yet to be done. The continuous relationship between the maternal glucose level and the prevalence of pregnancy complications is well‑documented. The list of outcomes includes congenital malformations, stillbirths, neonatal mortality, macrosomia, hypoglycemia, and many others. Several new therapeutic and monitoring tools have become available over the recent years, for example, short- and long‑acting insulin analogs, personal pumps, and continuous glucose monitoring systems. Interestingly, pregnancy planning and preconception education proved to be particularly effective in improving glycemic control in type 1 diabetic women and achieving therapeutic goals recommended by clinical guidelines. This resulted in the reduction of some maternal and neonatal pregnancy outcomes reported from various populations, but despite this remarkable progress the prevalence of the most common complication, neonatal macrosomia, is still substantially higher than in the newborns of mothers without diabetes. The likely causes of this phenomenon are short episodes of hyperglycemia, particularly postprandial ones, liberal diet, maternal obesity, and substantial weight gain during pregnancy - these potential reasons should be addressed in clinical practice. In the future, new therapeutic devices, such as close‑loop insulin pumps, may help further improve the prognosis in pregnant women with type 1 diabetes.


Histone H3K4 and K36 methylation, Chd1 and Rpd3S oppose the functions of Saccharomyces cerevisiae Spt4-Spt5 in transcription.
Spt4-Spt5, a general transcription elongation factor for RNA polymerase II, also has roles in chromatin regulation. However, the relationships between these functions are not clear. Previously, we isolated suppressors of a Saccharomyces cerevisiae spt5 mutation in genes encoding members of the Paf1 complex, which regulates several cotranscriptional histone modifications, and Chd1, a chromatin remodeling enzyme. Here, we show that this suppression of spt5 can result from loss of histone H3 lysines 4 or 36 methylation, or reduced recruitment of Chd1 or the Rpd3S complex. These spt5 suppressors also rescue the synthetic growth defects observed in spt5 mutants that also lack elongation factor TFIIS. Using a FLO8 reporter gene, we found that a chd1 mutation caused cryptic initiation of transcription. We further observed enhancement of cryptic initiation in chd1 isw1 mutants and increased histone acetylation in a chd1 mutant. We suggest that, as previously proposed for H3 lysine 36 methylation and the Rpd3S complex, H3 lysine 4 methylation and Chd1 function to maintain normal chromatin structures over transcribed genes, and that one function of Spt4-Spt5 is to help RNA polymerase II overcome the repressive effects of these histone modifications and chromatin regulators on transcription.


Desquamative interstitial pneumonia: Risk factors, laboratory and bronchoalveolar lavage findings, radiological and histopathological examination, clinical features, treatment and prognosis.
Desquamative interstitial pneumonia is a type of smoking-associated major idiopathic interstitial pneumonia, which is characterized by accumulation of alveolar macrophages in alveolar lumens and septa and develops secondary to mainly active or passive exposure to cigarette smoke. Desquamative interstitial pneumonia mostly occurs in male smokers in association with non-specific symptoms responsive to steroid therapy and has a better prognosis than usual interstitial pneumonia. To date, no large-scale clinical studies have been performed on desquamative interstitial pneumonia patients. Factors responsible for the scarcity of data on the clinical course of this condition include the retrospective nature of the available information as well as its rare occurrence. Despite this, a general consensus exists as to the nature of its symptoms, association with smoking, age and gender distribution, findings of respiratory function tests, steroid responsivity and mortality. The objective of the present review article was to report on desquamative interstitial pneumonia and to describe its etiology, risk factors and clinical features, as well as the laboratory, bronchoalveolar lavage, radiological and histopathological findings, and the treatment and prognosis of affected patients.


Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment.
Long-term treatment for atopic dermatitis (AD) using low dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent relapses. This 12-month, European, multicentre, randomized study investigated whether the proactive use of 0.1% tacrolimus ointment applied twice weekly can keep AD in remission and reduce the incidence of disease exacerbations (DE). During the initial open-label period, 257 adults with AD applied 0.1% tacrolimus ointment twice daily (b.i.d.) for up to 6 weeks to affected areas. When an Investigator Global Assessment (IGA) score of < or =2 was achieved, the patient entered the disease control period (DCP) and was randomized to either proactive tacrolimus (n = 116) or vehicle ointment (n = 108) twice weekly for 12 months. Exacerbations were treated with 0.1% tacrolimus ointment b.i.d. until an IGA < or =2 was regained, then randomized treatment was restarted. The primary endpoint was the number of DEs during the DCP that required a substantial therapeutic intervention. Proactive tacrolimus 0.1% ointment application significantly reduced the number of DEs requiring substantial therapeutic intervention (median difference 2; P < 0.001; Wilcoxon rank sum test), the percentage of DE treatment days (median difference: 15.2%; P < 0.001; Wilcoxon rank sum test) and increased the time to first DE (median 142 vs 15 days; P < 0.001; stratified log-rank test). The adverse event profile was similar for the two treatment approaches. A 12-month, twice weekly proactive tacrolimus ointment application was an effective treatment in most study patients which prevented, delayed and reduced the occurrence of AD exacerbations.


Association of retinal vessel pathology and brain atrophy in relapsing-remitting multiple sclerosis.
Optical coherence tomography angiography (OCTA) allows non-invasive assessment of retinal vessel structures. Thinning and loss of retinal vessels is evident in eyes of patients with multiple sclerosis (MS) and might be associated with a proinflammatory disease phenotype and worse prognosis. We investigated whether changes of the retinal vasculature are linked to brain atrophy and disability in MS. This study includes one longitudinal observational cohort (n=79) of patients with relapsing-remitting MS. Patients underwent annual assessment of the expanded disability status scale (EDSS), timed 25-foot walk, symbol digit modalities test (SDMT), retinal optical coherence tomography (OCT), OCTA, and brain MRI during a follow-up duration of at least 20 months. We investigated intra-individual associations between changes in the retinal architecture, vasculature, brain atrophy and disability. Eyes with a history of optic neuritis (ON) were excluded. We included 79 patients with a median disease duration of 12 (interquartile range 2 - 49) months and a median EDSS of 1.0 (0 - 2.0). Longitudinal retinal axonal and ganglion cell loss were linked to grey matter atrophy, cortical atrophy, and volume loss of the putamen. We observed an association between vessel loss of the superficial vascular complex (SVC) and both grey and white matter atrophy. Both observations were independent of retinal ganglion cell loss. Moreover, patients with worsening of the EDSS and SDMT revealed a pronounced longitudinal rarefication of the SVC and the deep vascular complex. ON-independent narrowing of the retinal vasculature might be linked to brain atrophy and disability in MS. Our findings suggest that retinal OCTA might be a new tool for monitoring neurodegeneration during MS.


The L2/HNK-1 Carbohydrate Epitope is Involved in the Preferential Outgrowth of Motor Neurons on Ventral Roots and Motor Nerves.
Based on the observation that in adult mice the carbohydrate epitope L2/HNK-1 is detectable on Schwann cells in ventral spinal roots, but only scarcely in dorsal roots (Martini et al., Dev. Biol., 129, 330 - 338, 1988), the possibility was investigated that the carbohydrate is involved in the outgrowth of regenerating motor neuron axons on peripheral nerve substrates expressing the epitope. To monitor whether the L2 carbohydrate remains present during the time periods in which regenerating axons penetrate the denervated distal nerve stumps, the expression of L2 in motor and sensory branches of the femoral nerve was investigated in normal animals and after a crush lesion. During the first two postoperative weeks, L2 immunoreactivity remained high in the myelinating Schwann cells of the motor branch, whereas L2 immunoreactivity was virtually absent in the sensory branch. In a first experimental approach, cryosections of ventral and dorsal spinal roots and of motor and sensory nerves of adult rats and mice were used as substrates for neurite outgrowth. Neurites of motor neurons from chicken embryos were approximately 35% longer after 30 h of maintenance on ventral roots than on dorsal roots. Neurites from sensory neurons had the same length on dorsal as on ventral motors and were as long as neurites from motor neurons grown on dorsal roots. L2 antibodies reduced neurite outgrowth of motor neurons on ventral roots but not on dorsal roots. Neurite outgrowth of sensory neurons on both roots was not altered by the antibodies. Neurite outgrowth of motor neurons on a mixture of the extracellular matrix glycoprotein laminin and the L2 carbohydrate-carrying glycolipid was significantly higher than on the laminin substrate mixture with GD1b ganglioside or sulphatide. L2 antibodies reduced neurite outgrowth of motor neurons by 50% on the L2 glycolipid, but not on GD1b or sulphatide. These observations indicate that the L2 carbohydrate promotes neurite outgrowth of motor neurons in vitro and may thus contribute to the preferential reinnervation of motor nerves by regenerating motor axons in vivo.


Salmonella SsrB activates a global regulon of horizontally acquired genes.
Salmonella enterica is a bacterial pathogen of humans that can proliferate within epithelial cells as well as professional phagocytes of the immune system. This ability requires an S. enterica specific locus termed Salmonella pathogenicity island 2 (SPI-2). SPI-2 encodes a type III secretion system that injects effectors encoded within the island into host cell cytosol to promote virulence. SsrAB is a two-component regulator encoded within SPI-2 that was assumed to activate SPI-2 genes exclusively. Here, it is shown that SsrB in fact activates a global regulon. At least 10 genes outside SPI-2 are SsrB regulated within epithelial and macrophage cells. Nine of these 10 SsrB-regulated genes outside SPI-2 reside within previously undescribed regions of the Salmonella genome. Most share no sequence homology with current database entries. However, one is remarkably homologous to human glucosyl ceramidase, an enzyme involved in the ceramide signalling pathway. The SsrB regulon is modulated by the two-component regulatory systems PhoP/PhoQ and OmpR/EnvZ, and is upregulated in the intracellular microenvironment.


The Bay Area Verbal Learning Test (BAVLT): Normative Data and the Effects of Repeated Testing, Simulated Malingering, and Traumatic Brain Injury.
Verbal learning tests (VLTs) are widely used to evaluate memory deficits in neuropsychiatric and developmental disorders. However, their validity has been called into question by studies showing significant differences in VLT scores obtained by different examiners. Here we describe the computerized Bay Area Verbal Learning Test (BAVLT), which minimizes inter-examiner differences by incorporating digital list presentation and automated scoring. In the 10-min BAVLT, a 12-word list is presented on three acquisition trials, followed by a distractor list, immediate recall of the first list, and, after a 30-min delay, delayed recall and recognition. In Experiment 1, we analyzed the performance of 195 participants ranging in age from 18 to 82 years. Acquisition trials showed strong primacy and recency effects, with scores improving over repetitions, particularly for mid-list words. Inter-word intervals (IWIs) increased with successive words recalled. Omnibus scores (summed over all trials except recognition) were influenced by age, education, and sex (women outperformed men). In Experiment 2, we examined BAVLT test-retest reliability in 29 participants tested with different word lists at weekly intervals. High intraclass correlation coefficients were seen for omnibus and acquisition scores, IWIs, and a categorization index reflecting semantic reorganization. Experiment 3 examined the performance of Experiment 2 participants when feigning symptoms of traumatic brain injury. Although 37% of simulated malingerers showed abnormal (p < 0.05) omnibus z-scores, z-score cutoffs were ineffective in discriminating abnormal malingerers from control participants with abnormal scores. In contrast, four malingering indices (recognition scores, primacy/recency effects, learning rate across acquisition trials, and IWIs) discriminated the two groups with 80% sensitivity and 80% specificity. Experiment 4 examined the performance of a small group of patients with mild or severe TBI. Overall, both patient groups performed within the normal range, although significant performance deficits were seen in some patients. The BAVLT improves the speed and replicability of verbal learning assessments while providing comprehensive measures of retrieval timing, semantic organization, and primacy/recency effects that clarify the nature of performance.


A Novel Variant of the FZD4 Gene in a Chinese Family Causes Autosomal Dominant Familial Exudative Vitreoretinopathy.
Familial exudative vitreoretinopathy (FEVR) is a complex hereditary eye disorder characterized by incomplete development of the retinal vasculature, thereby affecting retinal angiogenesis. In this study, a Chinese autosomal dominant FEVR pedigree was recruited. Ophthalmic examinations were performed, targeted next-generation sequencing was used to identify the causative gene, and Sanger sequencing was conducted to verify the candidate mutation. Co-segregation analysis was performed to evaluate pathogenicity. Semi-quantitative reverse transcription-PCR was applied to investigate the spatial and temporal expression patterns of the frizzled class receptor 4 (FZD4) gene in the mouse. A novel heterozygous, deleterious variant of the FZD4 gene, c.A749G (p.Y250C), was identified in this FEVR pedigree, which co-segregated with the clinical phenotype. The amino acid tyrosine (Y) is highly conserved both orthologously and paralogously. The FZD4 gene was highly expressed in the retina, sclera of the eye, ovary, kidney, and liver; ubiquitously expressed in other tissues; and highly expressed in 6 different developmental stages/times of retinal tissue. Our study is the first to identify that the novel heterozygous variant c.A749G (p.Y250C) in the FZD4 gene may be the disease-causing mutation in this FEVR family, extending its mutation spectrum. These findings further our understanding of the molecular pathogenesis of FEVR and will facilitate the development of methods for the diagnosis, prevention, and genetic counseling of this disease.


Coadministration of the Campylobacter jejuni N-Glycan-Based Vaccine with Probiotics Improves Vaccine Performance in Broiler Chickens.
Source attribution studies report that the consumption of contaminated poultry is the primary source for acquiring human campylobacteriosis. Oral administration of an engineered Escherichia coli strain expressing the Campylobacter jejuni N-glycan reduces bacterial colonization in specific-pathogen-free leghorn chickens, but only a fraction of birds respond to vaccination. Optimization of the vaccine for commercial broiler chickens has great potential to prevent the entry of the pathogen into the food chain. Here, we tested the same vaccination approach in broiler chickens and observed similar efficacies in pathogen load reduction, stimulation of the host IgY response, the lack of C. jejuni resistance development, uniformity in microbial gut composition, and the bimodal response to treatment. Gut microbiota analysis of leghorn and broiler vaccine responders identified one member of Clostridiales cluster XIVa, Anaerosporobacter mobilis, that was significantly more abundant in responder birds. In broiler chickens, coadministration of the live vaccine with A. mobilis or Lactobacillus reuteri, a commonly used probiotic, resulted in increased vaccine efficacy, antibody responses, and weight gain. To investigate whether the responder-nonresponder effect was due to the selection of a C. jejuni "supercolonizer mutant" with altered phase-variable genes, we analyzed all poly(G)-containing loci of the input strain compared to nonresponder colony isolates and found no evidence of phase state selection. However, untargeted nuclear magnetic resonance (NMR)-based metabolomics identified a potential biomarker negatively correlated with C. jejuni colonization levels that is possibly linked to increased microbial diversity in this subgroup. The comprehensive methods used to examine the bimodality of the vaccine response provide several opportunities to improve the C. jejuni vaccine and the efficacy of any vaccination strategy.IMPORTANCECampylobacter jejuni is a common cause of human diarrheal disease worldwide and is listed by the World Health Organization as a high-priority pathogen. C. jejuni infection typically occurs through the ingestion of contaminated chicken meat, so many efforts are targeted at reducing C. jejuni levels at the source. We previously developed a vaccine that reduces C. jejuni levels in egg-laying chickens. In this study, we improved vaccine performance in meat birds by supplementing the vaccine with probiotics. In addition, we demonstrated that C. jejuni colonization levels in chickens are negatively correlated with the abundance of clostridia, another group of common gut microbes. We describe new methods for vaccine optimization that will assist in improving the C. jejuni vaccine and other vaccines under development.