Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling.
Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE, causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke-knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E2 (PGE2). Treating the endothelial specific Dgke-knockout mice with a stable PGE2 analog was sufficient to reverse the clinical manifestations of thrombotic microangiopathy and proteinuria, possibly by suppressing the expression of matrix metalloproteinase 2 through PGE2-dependent upregulation of the chemokine receptor CXCR4. Our study reveals a complex array of autocrine signaling events downstream of VEGFR2 that are mediated by PGE2, that control endothelial activation and thrombogenic state, and that result in abnormalities of the glomerular filtration barrier.


Laparoscopic ventral rectopexy for faecal incontinence: equivalent benefit is seen in internal and external rectal prolapse.
An external rectal prolapse (ERP) is often associated with faecal incontinence, and surgery is the recommended therapy. It has been suggested that correction of a high grade internal rectal prolapse (HIRP) is also worthwhile for patients with faecal incontinence. The aim of the present study is to compare the results of laparoscopic ventral rectopexy (LVR) in patients with faecal incontinence associated with either an ERP or a HIRP. Consecutive patients suffering from faecal incontinence, who underwent a LVR between June 2010 and October 2012, were identified from a prospective database. All patients underwent preoperative defaecating proctography, anorectal manometry and ultrasound. Symptoms were assessed preoperatively and at 1 year after operation using a standardized questionnaire incorporating the Faecal Incontinence Severity Index (FISI; range 0-61) and the Gastrointestinal Quality of Life Index (GIQLI). LVR was performed in 50 incontinent patients with a HIRP, and in 41 patients with an ERP. Preoperatively, the FISI was higher in patients with HIRP (HIRP 42 versus ERP 30, P < 0.01). The recurrence rate at 1 year was similar in both groups (HIRP 6 % versus ERP 2 %, P = 0.156). The FISI scores were significantly reduced in both groups (HIRP 48 % versus ERP 50 %, both P < 0.01). GIQLI was equally improved in both groups (HIRP 17 % versus ERP 18 %, both P < 0.01). Laparoscopic ventral rectopexy for the treatment of faecal incontinence achieves equivalent outcomes in both patients with an external rectal prolapse or high grade internal rectal prolapse.


Substance abuse and intimate partner violence: treatment considerations.
Given the increased use of marital- and family-based treatments as part of treatment for alcoholism and other drug disorders, providers are increasingly faced with the challenge of addressing intimate partner violence among their patients and their intimate partners. Yet, effective options for clinicians who confront this issue are extremely limited. While the typical response of providers is to refer these cases to some form of batterers' treatment, three fundamental concerns make this strategy problematic: (1) most of the agencies that provide batterers' treatment only accept individuals who are legally mandated to complete their programs; (2) among programs that do accept nonmandated patients, most substance-abusing patients do not accept such referrals or drop out early in the treatment process; and (3) available evidence suggests these programs may not be effective in reducing intimate partner violence. Given these very significant concerns with the current referral approach, coupled with the high incidence of IPV among individuals entering substance abuse treatment, providers need to develop strategies for addressing IPV that can be incorporated and integrated into their base intervention packages.


The dynamic geometry of mass cell movements in animal morphogenesis.
There is an infinite number of interactions between morphogenetic processes of different time and space scales. How do these unfold in a regular series of mass morphogenetic movements to produce a basically simple and reproducible structure? I present a new morphogenetic concept -- the spatial unfolding (SU) of cell movements, whose definition rests on the correspondence between the continuous spatial series of cell shapes and the succession of changes in the shape of a single cell moving in an epithelial sheet whose shape is also subject to change. The change in the shape of moving cells is the only measure of their translocation both in space and time. The SU provides a morpho-dynamics description of mass cell movements which is completely independent of both an external coordinate system and external forces. The cell geometry of SU allows us to derive the future embryonic form from the actual one by a movement-shaping algorithm operating on the basis of positive and negative geometric feedbacks between the cell movement in the epithelial sheet plane and the epithelial sheet shaping, the feedback system providing a geometric alternative to Turing's self-organization via reaction-diffusion systems. Putting together histological, quantitative morphological and experimental data permits us to isolate four SU, each acting in morphogenesis as an irreducible whole, which seem to include all real examples of epithelial morphogenesis in multicellular animals, from Coelenterates to Chordates.


Conservation strategies for the long-term survival of the Cheetah Acinonyx jubatus by the Cheetah Conservation Fund, Windhoek.
The Cheetah Acinonyx jubatus is declining throughout its range because of loss of habitat, a declining prey base and competition with livestock interests. Throughout Africa there are less than 15 000 animals remaining. The largest wild population of Cheetahs is in Namibia, although in the last 12 years numbers have been reduced by half to c. 2500 animals. Significant declines have continued as farmers capture and remove Cheetahs as 'pests'. Established in 1990, the Cheetah Conservation Fund aims to secure habitats for the long-term survival of the species and its ecosystems. The primary focus of the Fund is working outside of the protected reserves with the local livestock farming communities to develop ways to reduce conflict between humans and Cheetahs. The Fund also conducts independent and collaborative research, disseminates information and recommends management techniques to farmers.


The preoperative serum ratio of total prostate specific antigen (PSA) to free testosterone (FT), PSA/FT index ratio, and prostate cancer. Results in 220 patients undergoing radical prostatectomy.
To evaluate associations of preoperative total prostate specific antigen (PSA) to free testosterone (FT), the PSA/FT index ratio, with features of pathology prostate cancer (PCA) and to investigate its prognostic potential in clustering the PCA population. After excluding criteria, the records of 220 patients who underwent radical prostatectomy (RP) were retrospectively reviewed. Serum samples of PSA, total testosterone (TT) and FT were collected at 8.00 A.M., one month after biopsies and before RP. The PSA/FT ratio was computed in the population of patients who were clustered in groups according to ranking intervals of the PSA/FT ratio which identified at least 4 clusters which were coded as A, B, C, and D. The independent associations of the PSA/FT index ratio were assessed by statistical methods and a two-sided P < 0.05 was considered to indicate statistical significance. TT correlated to FT which was a significant predictor of PSA in the population of patients who were subsequently clustered, according to increasing interval values of the PSA/FT index ratio, in groups that showed a stronger linear association of FT with PSA. The PSA/FT index ratio significantly associated with pathology features of prostate cancer such as pathology Gleason score (pGS), invasion of the seminal vesicles (pT3b), proportion of positive cores (P+) and proportion of cancer involving the volume of the prostate. In the population of patients, TT, PSA/FT index ratio and P+ independently associated with pGS ≥ 7 and pT3b; moreover, the odds ratio (OR) of the PSA/FT index ratio resulted 9.11 which was stronger than TT (OR = 1.11) and P+ (OR = 8.84). In the PCA population, TT, PSA/FT index ratio and P+ also independently associated with pT3b PCA; interestingly, the OR of PSA/FT index resulted 54.91 which was stronger than TT (OR = 1.31) and P+ (26.43). Preoperative PSA/FT index ratio is an independent strong factor which directly associates with aggressive features of pathology PCA; moreover, it might express prognostic potential for clustering the patient population in risk classes. Confirmatory studies are required.


An ultra-low-molecular-weight heparin, fondaparinux, to treat retinal vein occlusion.
Retinal vein occlusions may decrease visual acuity. There is no known therapy to treat ocular thrombosis. The authors used fondaparinux, an ultra-low-molecular-weight heparin, to treat 13 consecutive cases of recent-onset retinal vein occlusions. Two patients with renal insufficiency were not included. Eight central retinal vein occlusions and 5 branch retinal vein occlusions in 13 patients were treated with subcutaneous fondaparinux 2.5 mg once a day. The patients were seen every 2 weeks. Macular edema was treated with intravitreal injections of anti-vascular endothelial growth factor or steroids. Two patients elected to discontinue treatment. Of the remaining 11, 9 occlusions resolved in 1.5 to 13.5 months with rapid resolution of retinal edema and hemorrhage as soon as the occlusions resolved. One patient had a retinal vein that was still occluded after 8 months of therapy and 1 had retinal vein occlusion that partially resolved after 15 months of treatment. Of the 9 eyes with occlusions that resolved, visual acuity improved in 7. In 2, visual acuity decreased due to macular ischemia. Occlusion recurred in 1 2.5 months after the suspension of initial treatment. This patient is again being treated with fondaparinux 2.5 mg. No hemorrhaging occurred. Fondaparinux 2.5 mg can be given subcutaneously once a day to patients with recent-onset retinal vein occlusions without renal insufficiency. An occlusion may take a number of months to resolve. Once the vein occlusion has resolved, retinal edema and hemorrhage rapidly resolve and vision improves. Macular edema should be treated while waiting for the vein occlusion to resolve.


Aortic root geometry and stentless porcine valve competence.
The goal of this study was to characterize medium-term changes in aortic root geometry after stentless aortic valve replacement, the relationship between aortic sinotubular junction and the competence of stentless valves. A total of 205 consecutive patients (mean age 73+/-6 years; 120 men, 85 women) received a Freestyle stentless porcine aortic valve and were studied prospectively by echocardiography from 1 week to 5 years. Internal diameters of outflow tract, annulus, sinus, sinotubular junction, and ascending aortic root were measured at early ejection and indexed to stentless valve size. The degree of stentless valve regurgitation was semiquantified by color Doppler echocardiography. A total of 701 echocardiographic studies were obtained and analyzed; 73% showed a fully competent stentless valve (nAR) and 13% and 14%, respectively, showed a trivial (tAR) or mild (mAR) regurgitation. Sinotubular junction of tAR or mAR was significantly greater than that of nAR (111+/-1.9, 117+/-2.2 vs. 104+/-1.0, percentage of valve size, P<.001). A preoperative diagnosis of aortic regurgitation (110+/-2.6 vs. 104+/-1.0, percentage of valve size, P<.001) and 4 to 5-year follow-up time (116+/-2.2 vs. 107+/-2.9, percentage of valve size, P = .023) were associated with a greater sinotubular junction, although the incidence and mean grade of stentless valve regurgitation did not change significantly during the follow-up period. Up to medium-term follow-up evaluation, the incidence of moderate stentless aortic regurgitation is less than 5%. The nature of valve disease and age-related increase in sinotubular junction may have reduced the cusp coaptation area of the stentless valve and may predict the presence of a trivial or mild regurgitation. Understanding the interrelations between the stentless valve and remodeling of the aging aorta has important implications for both surgical technique and long-term follow-up outcome.


Incorporating intrinsic suppression in deep neural networks captures dynamics of adaptation in neurophysiology and perception.
Adaptation is a fundamental property of sensory systems that can change subjective experiences in the context of recent information. Adaptation has been postulated to arise from recurrent circuit mechanisms or as a consequence of neuronally intrinsic suppression. However, it is unclear whether intrinsic suppression by itself can account for effects beyond reduced responses. Here, we test the hypothesis that complex adaptation phenomena can emerge from intrinsic suppression cascading through a feedforward model of visual processing. A deep convolutional neural network with intrinsic suppression captured neural signatures of adaptation including novelty detection, enhancement, and tuning curve shifts, while producing aftereffects consistent with human perception. When adaptation was trained in a task where repeated input affects recognition performance, an intrinsic mechanism generalized better than a recurrent neural network. Our results demonstrate that feedforward propagation of intrinsic suppression changes the functional state of the network, reproducing key neurophysiological and perceptual properties of adaptation.


The role of early parenting in children's development of executive processes.
Using structural modeling, we examined the influence of mothers' verbal input that provided information about associations between objects and actions (scaffolding) at 3 and 4 years of age on children's 6-year executive processing skills. Executive processing skills were measured by search retrieval and independent goal-directed play tasks. A set of 4-year basic skills (language, memory, nonverbal problem solving) considered to be prerequisites for executive processing also were included. Patterns of influence across these variables were examined for 253 children who varied in neonatal complications and in their degree of risk for later developmental problems. Results showed that mothers' early verbal scaffolding at 3 years indirectly influenced both types of executive processing skills at 6 years by directly influencing children's language and nonverbal problem-solving skills at 4 years of age. Four-year scaffolding did not show direct influences on later executive processing skills. The provision of this form of maternal verbal input when children are rapidly developing language appears to support a set of basic skills necessary for later executive processing.


PEPVAC: a web server for multi-epitope vaccine development based on the prediction of supertypic MHC ligands.
Prediction of peptide binding to major histocompatibility complex (MHC) molecules is a basis for anticipating T-cell epitopes, as well as epitope discovery-driven vaccine development. In the human, MHC molecules are known as human leukocyte antigens (HLAs) and are extremely polymorphic. HLA polymorphism is the basis of differential peptide binding, until now limiting the practical use of current epitope-prediction tools for vaccine development. Here, we describe a web server, PEPVAC (Promiscuous EPitope-based VACcine), optimized for the formulation of multi-epitope vaccines with broad population coverage. This optimization is accomplished through the prediction of peptides that bind to several HLA molecules with similar peptide-binding specificity (supertypes). Specifically, we offer the possibility of identifying promiscuous peptide binders to five distinct HLA class I supertypes (A2, A3, B7, A24 and B15). We estimated the phenotypic population frequency of these supertypes to be 95%, regardless of ethnicity. Targeting these supertypes for promiscuous peptide-binding predictions results in a limited number of potential epitopes without compromising the population coverage required for practical vaccine design considerations. PEPVAC can also identify conserved MHC ligands, as well as those with a C-terminus resulting from proteasomal cleavage. The combination of these features with the prediction of promiscuous HLA class I ligands further limits the number of potential epitopes. The PEPVAC server is hosted by the Dana-Farber Cancer Institute at the site http://immunax.dfci.harvard.edu/PEPVAC/.


A study on investigating unplanned readmission patterns.
To explain frequent hospital readmissions, this study aimed to determine whether definable subtypes exist within a cohort of subjects with chronic illness with regard to factors associated with a patient's readmission patterns and to compare whether these factors vary between subjects in groups with different profiles. A descriptive correlational survey was conducted and data were collected by using a structured questionnaire. Seventy-four readmitted subjects were recruited in three general hospitals in Hong Kong. Five outcome variables were employed in the study: predisposing characteristic, need factors, health behaviour, health status or outcomes and enabling resources. A cluster analysis yielded two clusters. Each cluster represented a different profile of the sample on patient use of healthcare services. Cluster A consisted of 41.9% (n = 31) and Cluster B consisted of 58.1% (n = 43) of the patients. Cluster A patients, more of whom were male, were younger, more educated, had higher activities of daily living scores and fewer of them had received community nurse services than patients of Cluster B. Cluster A patients (32.3%) had more than one readmission record within 28 days than Cluster B patients (9.3%, p = 0.017). Our study shows that community nurse services can reduce the rate at which they are readmitted a second time. However, such services may have a positive effect only on a group of patients whose profile is similar to the patients in Cluster B and not for patients such as those in Cluster A. A clear profile may help healthcare policy makers make appropriate strategies to target a specific group of patients to reduce their readmission rates. The identification of risk for future healthcare use could enable better targeting of interventional strategies within these groups. The results of this study might provide hospital managers with a model to design specified interventions to reduce unplanned hospital readmissions for each profile group.


Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy.
Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone's adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone's promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without α-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone's effects on prostate, but did not affect testosterone's anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy.


Divergent MLS1 Promoters Lie on a Fitness Plateau for Gene Expression.
Qualitative patterns of gene activation and repression are often conserved despite an abundance of quantitative variation in expression levels within and between species. A major challenge to interpreting patterns of expression divergence is knowing which changes in gene expression affect fitness. To characterize the fitness effects of gene expression divergence, we placed orthologous promoters from eight yeast species upstream of malate synthase (MLS1) in Saccharomyces cerevisiae As expected, we found these promoters varied in their expression level under activated and repressed conditions as well as in their dynamic response following loss of glucose repression. Despite these differences, only a single promoter driving near basal levels of expression caused a detectable loss of fitness. We conclude that the MLS1 promoter lies on a fitness plateau whereby even large changes in gene expression can be tolerated without a substantial loss of fitness.


Prescription drug accessibility and affordability in the United States and abroad.
This issue brief contrasts prescription drug access, affordability, and costs in the United States with six other high-income countries, drawing from Commonwealth Fund survey data of patient experiences as well as international spending and pricing data. The analysis reveals that Americans, particularly the relatively young and healthy, are more likely to use prescription drugs than are residents of Australia, Canada, Germany, the Netherlands, New Zealand, and the United Kingdom, but they also experience more financial barriers in accessing medications and spend more out-of-pocket for prescriptions. In the U.S., there are also larger income-related inequities in pharmaceutical use. Despite access barriers and disparities, spending per person in the U.S. is far higher, likely the result of paying higher prices for similar medications and using a more expensive mix of drugs. The authors say that value-based benefit designs, reference pricing, and group purchasing could reduce financial barriers and keep down pharmaceutical spending.


Chronic vagus nerve stimulation for treatment-resistant depression decreases resting ventromedial prefrontal glucose metabolism.
Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treatment-resistant depression (TRD). Its mechanism of action is not fully understood. Longitudinal measurement of changes in brain metabolism associated with VNS can provide insights into this new treatment modality. Eight severely depressed outpatients who were highly treatment-resistant underwent electrical stimulation of the left vagus nerve for approximately one year. The main outcome measures were resting regional brain glucose uptake measured with positron emission tomography (PET) and the 24-item Hamilton Depression Scale. The most significant and extensive change over one year of chronic VNS localized to the ventromedial prefrontal cortex extending from the subgenual cingulate to the frontal pole. This region continued to decline in metabolism even toward the end of the study. Clinically, this cohort showed a trend for improvement. No correlations surfaced between change in glucose uptake and depression scores. However, the sample size was small; none remitted; and the range of depression scores was limited. Chronic VNS as adjunctive therapy in patients with severe TRD produces protracted and robust declines in resting brain activity within the ventromedial prefrontal cortex, a network with dense connectivity to the amygdala and structures monitoring the internal milieu.


Controlled shape deformation of bilayer films with tough adhesion between nanocomposite hydrogels and polymer substrates.
Shape-shifting materials have received increasing attention owing to their promising applications in soft robotics, biomedical devices, actuators, morphing aircraft and so on. However, their practical applications are limited due to their weak mechanical strength, low interfacial adhesion and complex preparation method. In this paper, bilayer films were synthesized by in situ one-step forming soft and water-swellable nanocomposite hydrogels on the surface of the rigid and nonresponsive poly(ethylene terephthalate) (PET) film without any surface modification. The strong interfacial toughness between the hydrogel layer and the PET layer, the high swelling ability of the soft hydrogel layer, and the high strength of the rigid PET film endowed the bilayer film with excellent self-bending behaviour. The shape deformation of the bilayer films can be controlled by adjusting the geometry parameters of the bilayer film, such as the hydrogel thickness, the aspect ratio and the width of the bilayer film. Moreover, the bilayer film exhibited excellent reversible bidirectional self-bending behaviour. In addition, the mechanisms for driving the shape transformation were discussed. We believe this work will provide a promising and simple strategy to develop novel responsive materials with controlled shape deformation.


Transitioning From Community-Based to Institutional Long-term Care: Comparing 1915(c) Waiver and PACE Enrollees.
To compare the risk of long-term nursing home (NH) admission and the level of functional and cognitive impairment at the time of long-term NH admission in the Program of All-Inclusive Care for the Elderly (PACE) and in 1915(c) aged and aged and disabled waiver programs. Cohorts of new waiver and PACE enrollees in 12 states were identified (in 2005-2007) and followed (through 2009) using the Medicaid Analytic Extract and the Minimum Data Set. Individual-level outcomes of interest were time from waiver or PACE enrollment to long-term (90+ days) NH admission and functional (29-point activities of daily living [ADL]) and cognitive (7-point Cognitive Performance Scale [CPS]) impairment at NH admission. An overall measure of impairment was also created and categorized as low (ADL < 17 and CPS < 3) versus high (ADL ≥ 17 or CPS ≥ 3). The key independent variable was enrollment in PACE versus waiver program. County-level covariates were included. Analyses employed multivariable models including competing risk proportional hazard and linear and logistic regressions. Compared with waiver enrollees, PACE enrollees had 31% lower risk of long-term NH admission (p < .001). At NH admission, they were overall significantly (p < .0001) more cognitively impaired (0.34 point), with 55% higher odds of severe (CPS ≥ 4) cognitive impairment (p < .001) and 45% higher odds of having overall high impairment (p = .003). PACE may be more effective than 1915(c) aged and aged and disabled waiver programs in reducing long-term NH use and may be particularly well suited to supporting cognitively impaired individuals, enabling them to remain in the community longer.


Enhancing Working Memory Training with Transcranial Direct Current Stimulation.
Working memory (WM) is a fundamental cognitive ability that supports complex thought but is limited in capacity. Thus, WM training interventions have become very popular as a means of potentially improving WM-related skills. Another promising intervention that has gained increasing traction in recent years is transcranial direct current stimulation (tDCS), a noninvasive form of brain stimulation that can modulate cortical excitability and temporarily increase brain plasticity. As such, it has the potential to boost learning and enhance performance on cognitive tasks. This study assessed the efficacy of tDCS to supplement WM training. Sixty-two participants were randomized to receive either right prefrontal, left prefrontal, or sham stimulation with concurrent visuospatial WM training over the course of seven training sessions. Results showed that tDCS enhanced training performance, which was strikingly preserved several months after training completion. Furthermore, we observed stronger effects when tDCS was spaced over a weekend break relative to consecutive daily training, and we also demonstrated selective transfer in the right prefrontal group to nontrained tasks of visual and spatial WM. These findings shed light on how tDCS may be leveraged as a tool to enhance performance on WM-intensive learning tasks.


Modified joint transform correlator binarized by error-diffusion. I. Spatially constant noise-dependent range limit.
Two error-diffusion-based binarization methods for joint transform correlator configurations, which adaptively take into account the effects of input-additive white Gaussian noise, are analyzed. Before binarization, the operations performed upon the joint power spectrum are either truncation and normalization or subtraction of a noise pedestal followed by truncation and normalization. The noise-pedestal value is defined as the measurable estimate of the noise power spectral density. Truncation and normalization are carried out with a spatially constant noise-dependent range limit, based on the statistical properties of the noise, and the noise-pedestal value. All required parameters, dependent on the input-noise level, can be measured from the joint power spectrum distribution and are updated for every new input scene. A computer-simulation comparison of correlation-peak characteristics demonstrates the advantages of the suggested approaches. Optical experiments with compatible results are also presented.


Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis.
The EULAR (European League Against Rheumatism) Scleroderma Trials and Research Group (EUSTAR) has identified preliminary criteria for very early diagnosis of systemic sclerosis (SSc). Our aim was to assess the prevalence of each proposed diagnostic item in a large observational patient cohort with Raynaud's phenomenon (RP). Baseline data of 469 RP patients enrolled into the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) cohort are presented. 68% of all RP patients were antinuclear antibody (ANA) positive. ANA+ RP patients more frequently had previous or current puffy fingers (PuFi) (38.5% and 23.3%, p<0.01) and an SSc pattern on nailfold capillaroscopy (NC) (53.6% and 13.4%, p<0.001) than ANA- patients. Telangiectasia, current digital ulcers and digital pitting scars were also commoner in ANA+ RP patients. 38% of ANA+ patients presented with all three features, which should raise suspicion of very early SSc (ANA+RP+PuFi constitutes a 'red flag'). These patients more frequently exhibited an NC SSc pattern, sclerodactyly and telangiectases compared to ANA+ patients without PuFi. Almost 90% of patients with 'red flags' had anti-centromere or anti-topoisomerase I antibodies and/or an NC SSc pattern, and fulfilled the EUSTAR criteria for very early SSc. Previous or current PuFi were present in 23.3% of ANA- RP patients, eight of whom also had an NC SSc pattern. In addition to well-characterised predictive factors, PuFi is an important sign raising suspicion for underlying very early SSc in patients with RP. The relevance of PuFi in ANA- RP patients should be clarified.


The N550 component of the evoked K-complex: a modality non-specific response?
A large amplitude late negative deflection peaking between 500 and 650 ms is observable in the averaged K-complex wave-form. This peak is thus often labelled the N550. 'N550' appears during stage 2 and is maintained into slow wave sleep but is not apparent during REM. Most studies have employed auditory stimuli to elicit the K-complex. Two experiments were run to examine the effects of stimulus modality on the topographical distribution of the N550. In the first experiment, the K-complexes were elicited in an auditory oddball procedure. In the second experiment, K-complexes were elicited by respiratory occlusions. Twenty-nine channel recordings were used to increase spatial resolution. N550 was substantially larger in the average of trials containing K-complexes than in trials in which a K-complex could not be identified. N550 varied inversely in amplitude with the probability of accordance of the stimulus. The topographic distribution of the N550 was consistent between experiments. It was bilaterally symmetrical and was maximal over fronto-central regions of the scalp. The results indicate that the N550 reflects the activity of a modality non-specific, sleep dependent generator that responds to both interoceptive and external stimulation.


Analysis & commentary. Unleashing nurse practitioners' potential to deliver primary care and lead teams.
Highly skilled primary care is a hallmark of high-performing health care systems. We examine nurse practitioners' role in delivering primary care and the effects of current restrictions on their ability to practice. By resolving differences between states' individual scope-of-practice regulations, we can fully benefit from the skills of advanced-practice nurses in all fifty states. We recommend substantive changes in the way health care professionals in all disciplines are trained, and in their roles, so that patients can receive appropriate and cost-effective care from skilled and fully functional health care teams.


Ancient animal microRNAs and the evolution of tissue identity.
The spectacular escalation in complexity in early bilaterian evolution correlates with a strong increase in the number of microRNAs. To explore the link between the birth of ancient microRNAs and body plan evolution, we set out to determine the ancient sites of activity of conserved bilaterian microRNA families in a comparative approach. We reason that any specific localization shared between protostomes and deuterostomes (the two major superphyla of bilaterian animals) should probably reflect an ancient specificity of that microRNA in their last common ancestor. Here, we investigate the expression of conserved bilaterian microRNAs in Platynereis dumerilii, a protostome retaining ancestral bilaterian features, in Capitella, another marine annelid, in the sea urchin Strongylocentrotus, a deuterostome, and in sea anemone Nematostella, representing an outgroup to the bilaterians. Our comparative data indicate that the oldest known animal microRNA, miR-100, and the related miR-125 and let-7 were initially active in neurosecretory cells located around the mouth. Other sets of ancient microRNAs were first present in locomotor ciliated cells, specific brain centres, or, more broadly, one of four major organ systems: central nervous system, sensory tissue, musculature and gut. These findings reveal that microRNA evolution and the establishment of tissue identities were closely coupled in bilaterian evolution. Also, they outline a minimum set of cell types and tissues that existed in the protostome-deuterostome ancestor.


Perfectionistic self-presentation, body image, and eating disorder symptoms.
A specific model for eating disorder symptoms involving perfectionistic self-presentation and two different moderators (i.e., body image evaluation and body image investment) was tested. Participants completed measures of perfectionistic self-presentation, body image dysfunction, and eating disorder symptoms. Findings indicated that all three dimensions of perfectionistic self-presentation were associated with eating disorder symptoms. Results also showed that perfectionistic self-presentation predicted eating disorder symptoms in women who were dissatisfied with their bodies, but that it did not predict eating problems in women who liked their bodies and felt there was little or no discrepancy between their actual and ideal appearances. Body image investment did not moderate the relationship between perfectionistic self-presentation and eating disorder symptoms, suggesting that ego-involvement alone is insufficient to promote eating disturbance in the context of perfectionism. The importance of self-presentation components of perfectionism and specific body image difficulties in predicting eating disorder symptoms are discussed.


Setting up and optimization of membrane protein simulations.
In this paper we describe a method for setting up an atomistic simulation of a membrane protein in a hydrated lipid bilayer and report the effect of differing electrostatic parameters on the drift in the protein structure during the subsequent simulation. The method aims to generate a suitable cavity in the interior of a lipid bilayer, using the solvent-accessible surface of the protein as a template, during the course of a short steered molecular dynamics simulation of a solvated lipid membrane. This is achieved by a two-stage process: firstly, lipid molecules whose headgroups are inside a cylindrical volume equivalent to that defined by the protein surface are removed; then the protein-lipid interface is optimized by applying repulsive forces perpendicular to the protein surface, and of gradually increased magnitude, to the remaining lipid atoms inside the volume occupied by the protein surface until it is emptied. The protein itself may then be inserted. Using the bacterial membrane proteins KcsA and FhuA as test cases, we show how the method achieves the formation of a suitable cavity in the interior of a dimyristoylphosphatidylcholine lipid bilayer without perturbing the configuration of the non-interfacial regions of the previously equilibrated lipid bilayer, even in cases of membrane proteins with irregular geometrical shapes. In addition, we compare subsequent simulations in which the long-range electrostatic interactions are treated via either a cut-off or a particle-mesh Ewald method. The results show that the drift from the initial structure is less in the latter case, especially for KcsA and for the non-core secondary structural elements (i.e. surface loops) of both proteins.


Treatment of immune-mediated, dysimmune neuropathies.
This review focuses on the actual status and recent advances in the treatment of immune-mediated neuropathies, including: Guillain-Barre syndrome (GBS) with its subtypes acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, Miller Fisher syndrome, and acute pandysautonomia; chronic inflammatory demyelinating polyneuropathy (CIDP) with its subtypes classical CIDP, CIDP with diabetes, CIDP/monoclonal gammopathy of undetermined significance (MGUS), sensory CIDP, multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy or Lewis-Sumner syndrome, multifocal acquired sensory and motor neuropathy, and distal acquired demyelinating sensory neuropathy; IgM monoclonal gammopathies with its subtypes Waldenstrom's macroglobulinemia, myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome, mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome, and MGUS. Concerning the treatment of GBS, there is no significant difference between intravenous immunoglobulins (IVIG), plasma exchange or plasma exchange followed by IVIG. Because of convenience and absent invasiveness, IVIG are usually preferred. In treating CIDP corticosteroids, IVIG, or plasma exchange are equally effective. Despite the high costs and relative lack of availability, IVIG are preferentially used. For the one-third of patients, who does not respond, other immunosuppressive options are available. In MMN IVIG are the treatment of choice. Inadequate response in 20% of the patients requires adjunctive immunosuppressive therapies. Neuropathies with IgM monoclonal gammopathy may respond to various chemotherapeutic agents, although the long-term effects are unknown. In addition, such treatment may be associated with serious side effects. Recent data support the use of rituximab, a monoclonal antibody against the B-cell surface-membrane-marker CD20.


Treating those found incompetent for execution: ethical chaos with only one solution.
In early 1988 the population on America's death rows climbed above the 2,000 mark for the first time in history. In 1986 the United States Supreme Court firmly stated that the Constitution will have been violated if any of these prisoners is put to death while mentally incompetent for execution. In this article we discuss the case of Gary Alvord, the only inmate to be formally found incompetent for execution in modern times. Interviews with psychiatrists and mental health professionals at the Florida psychiatric hospital where Alvord was treated between 1984 and 1987 reveal much ambivalence and anger about the case. We conclude that, out of respect for the rights of these mental health professionals and the ethical codes of their professions, any prisoner found incompetent for execution should have his or her death sentence commuted to long-term imprisonment before treatment is requested or given.


Modeling Cortisol Daily Rhythms of Family Caregivers of Individuals With Dementia: Daily Stressors and Adult Day Services Use.
The study examined the typical diurnal cortisol trajectory and its differential associations with an intervention, the adult day services (ADS) use, among a sample of family caregivers who experienced high levels of daily stress. On hundred and sixty-five caregivers of individuals with dementia completed an 8-day diary on daily stressors, positive events, sleep quality, and ADS use. The caregivers also provided five saliva samples on each diary day. Daily cortisol trajectories were modeled as a function of time elapsed since awakening, and three spline growth curve models were fit to the cortisol data. Based on the best-fitting linear spline model, the effect of daily ADS use was examined at both daily and person levels. Covariates included daily experiences and other caregiving characteristics. On ADS days, caregivers had a steeper cortisol awakening response (CAR) slope and a steeper morning decline. ADS use remained significant after controlling for covariates at both daily and person levels. The findings suggested potential biophysiological benefits of daily ADS use for a sample that was under chronic stress and high levels of daily stress.


Gene overlap and site-specific attenuation of transcription of the viral polymerase L gene of human respiratory syncytial virus.
Sequence analysis of the gene encoding polymerase L protein of respiratory syncytial virus showed that L-gene transcription initiates within its upstream neighbor, the gene encoding the 22-kDa protein 22K. This is an exception to the canonical mode of sequential transcription of nonoverlapping genes described for other nonsegmented negative-strand RNA viruses. As a consequence of the gene overlap, the termination/polyadenylylation signal for the 22K gene is located at nucleotides 56-68 within the L gene. L-gene transcription yielded two RNAs: an abundant, truncated, polyadenylylated transcript resulting from termination at the internal signal and a markedly less abundant large polyadenylylated transcript representing the complete L gene. This result showed that the internal termination/polyadenylylation signal is an attenuator of L-gene transcription.


GRASS: a generic algorithm for scaffolding next-generation sequencing assemblies.
The increasing availability of second-generation high-throughput sequencing (HTS) technologies has sparked a growing interest in de novo genome sequencing. This in turn has fueled the need for reliable means of obtaining high-quality draft genomes from short-read sequencing data. The millions of reads usually involved in HTS experiments are first assembled into longer fragments called contigs, which are then scaffolded, i.e. ordered and oriented using additional information, to produce even longer sequences called scaffolds. Most existing scaffolders of HTS genome assemblies are not suited for using information other than paired reads to perform scaffolding. They use this limited information to construct scaffolds, often preferring scaffold length over accuracy, when faced with the tradeoff. We present GRASS (GeneRic ASsembly Scaffolder)-a novel algorithm for scaffolding second-generation sequencing assemblies capable of using diverse information sources. GRASS offers a mixed-integer programming formulation of the contig scaffolding problem, which combines contig order, distance and orientation in a single optimization objective. The resulting optimization problem is solved using an expectation-maximization procedure and an unconstrained binary quadratic programming approximation of the original problem. We compared GRASS with existing HTS scaffolders using Illumina paired reads of three bacterial genomes. Our algorithm constructs a comparable number of scaffolds, but makes fewer errors. This result is further improved when additional data, in the form of related genome sequences, are used. GRASS source code is freely available from http://code.google.com/p/tud-scaffolding/. Supplementary data are available at Bioinformatics online.


AuNP-DG: deoxyglucose-labeled gold nanoparticles as X-ray computed tomography contrast agents for cancer imaging.
To study the feasibility of using 2-deoxy-D-glucose (2-DG)-labeled gold nanoparticle (AuNP-DG) as a computed tomography (CT) contrast agent with tumor targeting capability through in vitro experiments. Gold nanoparticles (AuNP) were fabricated and were conjugated with 2-deoxy-D-glucose. The human alveolar epithelial cancer cell line, A-549, was chosen for the in vitro cellular uptake assay. Two groups of cell samples were incubated with the AuNP-DG and the unlabeled AuNP, respectively. Following the incubation, the cells were washed with sterile PBS to remove the excess gold nanoparticles and spun to cell pellets using a centrifuge. The cell pellets were imaged using a microCT scanner immediately after the centrifugation. The reconstructed CT images were analyzed using a commercial software package. Significant contrast enhancement in the cell samples incubated with the AuNP-DG with respect to the cell samples incubated with the unlabeled AuNP was observed in multiple CT slices. Results from this study demonstrate enhanced uptake of 2-DG-labeled gold nanoparticle by cancer cells in vitro and warrant further experiments to study the exact molecular mechanism by which the AuNP-DG is internalized and retained in the tumor cells.


Efficacy and tolerability of oral stevioside in patients with mild essential hypertension: a two-year, randomized, placebo-controlled study.
Stevioside, a natural glycoside isolated from the plant Stevia rebaudiana Bertoni, has been used as a commercial sweetening agent in Japan and Brazil for >20 years. Previous animal and human studies have indicated that stevioside has an antihypertensive effect. This study was undertaken to investigate the long-term (2-year) efficacy and tolerability of stevioside in patients with mild essential hypertension. Secondary objectives were to determine the effects of stevioside on left ventricular mass index (LVMI) and quality of life (QOL). This was a multicenter, randomized, double-blind, placebo-controlled trial in Chinese men and women aged between 20 and 75 years with mild essential hypertension (systolic blood pressure [SBP] 140-159 mm Hg and diastolic blood pressure [DBP] 90-99 mm Hg). Patients took capsules containing 500 mg stevioside powder or placebo 3 times daily for 2 years. Blood pressure was measured at monthly clinic visits; patients were also encouraged to monitor blood pressure at home using an automated device. LVMI was determined by 2-dimensional echocardiography at baseline and after 1 and 2 years of treatment. QOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey. Electrocardiographic, laboratory, and QOL parameters were assessed at the beginning of treatment, and at 6 months, 1 year, and 2 years. One hundred seventy-four patients (87 men, 87 women) were enrolled in the study, and 168 completed it: 82 (42 men, 40 women; mean [SD] age, 52 [7] years) in the stevioside group and 86 (44 women, 42 men; mean age, 53 [7] years) in the placebo group. After 2 years, the stevioside group had significant decreases in mean (SD) SBP and DBP compared with baseline (SBP, from 150 [7.3] to 140 [6.8] mm Hg; DBP, from 95 [4.2] to 89 [3.2] mm Hg; P < 0.05) and compared with placebo (P < 0.05). Based on patients' records of self-monitored blood pressure, these effects were noted beginning approximately 1 week after the start of treatment and persisted throughout the study. There were no significant changes in body mass index or blood biochemistry, and the results of laboratory tests were similar in the 2 groups throughout the study. No significant difference in the incidence of adverse effects was noted between groups, and QOL scores were significantly improved overall with stevioside compared with placebo (P < 0.001). Neither group had a significant change in mean LVMI. However, after 2 years, 6 of 52 patients (11.5%) in the stevioside group had left ventricular hypertrophy (LVH), compared with 17 of 50 patients (34.0%) in the placebo group (P < 0.001). Of those who did not have LVH at baseline, 3 of 46 patients (6.5%) in the stevioside group had developed LVH after 2 years, compared with 9 of 37 patients (24.3%) in the placebo group (P < 0.001). In this 2-year study in Chinese patients with mild hypertension, oral stevioside significantly decreased SBP and DBP compared with placebo. QOL was improved, and no significant adverse effects were noted.


Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter.
Amiodarone is effective in maintaining sinus rhythm in atrial fibrillation but is associated with potentially serious toxic effects. Dronedarone is a new antiarrhythmic agent pharmacologically related to amiodarone but developed to reduce the risk of side effects. In two identical multicenter, double-blind, randomized trials, one conducted in Europe (ClinicalTrials.gov number, NCT00259428 [ClinicalTrials.gov] ) and one conducted in the United States, Canada, Australia, South Africa, and Argentina (termed the non-European trial, NCT00259376 [ClinicalTrials.gov] ), we evaluated the efficacy of dronedarone, with 828 patients receiving 400 mg of the drug twice daily and 409 patients receiving placebo. Rhythm was monitored transtelephonically on days 2, 3, and 5; at 3, 5, 7, and 10 months; during recurrence of arrhythmia; and at nine scheduled visits during a 12-month period. The primary end point was the time to the first recurrence of atrial fibrillation or flutter. In the European trial, the median times to the recurrence of arrhythmia were 41 days in the placebo group and 96 days in the dronedarone group (P=0.01). The corresponding durations in the non-European trial were 59 and 158 days (P=0.002). At the recurrence of arrhythmia in the European trial, the mean (+/-SD) ventricular rate was 117.5+/-29.1 beats per minute in the placebo group and 102.3+/-24.7 beats per minute in the dronedarone group (P<0.001); the corresponding rates in the non-European trial were 116.6+/-31.9 and 104.6+/-27.1 beats per minute (P<0.001). Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group. Dronedarone was significantly more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrence of arrhythmia.


Fibroblast phenotype in male carriers of FMR1 premutation alleles.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder among carriers of premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The clinical features of FXTAS, as well as various forms of clinical involvement in carriers without FXTAS, are thought to arise through a direct toxic gain of function of high levels of FMR1 mRNA containing the expanded CGG repeat. Here we report a cellular endophenotype involving increased stress response (HSP27, HSP70 and CRYAB) and altered lamin A/C expression/organization in cultured skin fibroblasts from 11 male carriers of premutation alleles of the FMR1 gene, including six patients with FXTAS and five premutation carriers with no clinical evidence of FXTAS, compared with six controls. A similar abnormal cellular phenotype was found in CNS tissue from 10 patients with FXTAS. Finally, there is an analogous abnormal cellular distribution of lamin A/C isoforms in knock-in mice bearing the expanded CGG repeat in the murine Fmr1 gene. These alterations are evident even in mouse embryonic fibroblasts, raising the possibility that, in humans, the expanded-repeat mRNA triggers pathogenic mechanisms early in development, thus providing a molecular basis for the neurodevelopmental abnormalities observed in some children and clinical symptoms in some adults who are carriers of premutation FMR1 alleles. Cellular dysregulation in fibroblasts represents a novel and highly advantageous model for investigating disease pathogenesis in premutation carriers and for quantifying and monitoring disease progression. Fibroblast studies may also prove useful in screening and testing the efficacy of therapeutic interventions.


A spastic paraplegia mouse model reveals REEP1-dependent ER shaping.
Axonopathies are a group of clinically diverse disorders characterized by the progressive degeneration of the axons of specific neurons. In hereditary spastic paraplegia (HSP), the axons of cortical motor neurons degenerate and cause a spastic movement disorder. HSP is linked to mutations in several loci known collectively as the spastic paraplegia genes (SPGs). We identified a heterozygous receptor accessory protein 1 (REEP1) exon 2 deletion in a patient suffering from the autosomal dominantly inherited HSP variant SPG31. We generated the corresponding mouse model to study the underlying cellular pathology. Mice with heterozygous deletion of exon 2 in Reep1 displayed a gait disorder closely resembling SPG31 in humans. Homozygous exon 2 deletion resulted in the complete loss of REEP1 and a more severe phenotype with earlier onset. At the molecular level, we demonstrated that REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein that resides in the ER. We further show that Reep1 expression was prominent in cortical motor neurons. In REEP1-deficient mice, these neurons showed reduced complexity of the peripheral ER upon ultrastructural analysis. Our study connects proper neuronal ER architecture to long-term axon survival.


The oral contraceptive pill effectively permits cycle batching for an intermittent in vitro fertilization programme in Trinidad and Tobago.
Assisted reproductive technology (ART) in small island states like Trinidad and Tobago is usually provided in batches so as to minimize the cost of providing the service. As a result, patients 'cycles have to be synchronized in order to coincide with the arrival of a visiting embryologist. This is a retrospective study which evaluates the experience of pre-treatment with an oral contraceptive pill (OCP) as a means of batching cycles for an intermittent ART programme. Seventy-four in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles in which OCP usage was employed (Group A), were compared with 121 cycles which did not require pharmaceutical manipulation (Group B). In both groups more than 50% of women were older than 36-years. Two cycles were cancelled in Group A and seven in Group B, because of poor ovarian response. Although the pregnancy rate per treatment cycle was higher in Group A than in Group B (26.3% vs 17.3%), this difference was not significant. More spontaneous miscarriages occurred in the non-OCP women and ovarian cyst formation was more common in these women. The authors experience indicates that the OCP is a simple, cheap and efficient means of batching patients for an intermittent ART programme and can be utilized in other small ART centres.


Efficacy and Safety of Liraglutide 3.0 mg in Individuals With Overweight or Obesity and Type 2 Diabetes Treated With Basal Insulin: The SCALE Insulin Randomized Controlled Trial.
Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population. Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) Insulin was a 56-week, randomized, double-blind, placebo-controlled, multinational, multicenter trial in individuals with overweight or obesity and type 2 diabetes treated with basal insulin and ≤2 oral antidiabetic drugs. Individuals were randomized to liraglutide 3.0 mg (n = 198) or placebo (n = 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was -5.8% for liraglutide 3.0 mg versus -1.5% with placebo (estimated treatment difference -4.3% [95% CI -5.5; -3.2]; P < 0.0001). With liraglutide 3.0 mg, 51.8% of individuals achieved ≥5% weight loss versus 24.0% with placebo (odds ratio 3.41 [95% CI 2.19; 5.31]; P < 0.0001). Liraglutide 3.0 mg was associated with significantly greater reductions in mean HbA1c and mean daytime glucose values and less need for insulin versus placebo, despite a treat-to-glycemic-target protocol. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No new safety or tolerability issues were observed. In individuals with overweight or obesity and insulin-treated type 2 diabetes, liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss and improved glycemic control despite lower doses of basal insulin and without increases in hypoglycemic events.


Effect of candidate vaginally-applied microbicide compounds on recognition of antigen by CD4+ and CD8+ T lymphocytes.
Vaginally applied antimicrobial compounds (microbicides) are being developed as an alternative method for preventing the spread of sexually transmitted diseases. In addition to identifying compounds effective against a spectrum of sexually transmitted pathogens, it will be important to ensure that these compounds are safe. Avoiding toxicity, inflammatory responses, or alteration of the function of resident immune cells are important considerations for the development of vaginally applied microbicides. Studies were performed with two classes of candidate microbicide compounds to determine if they would interfere with the recognition of antigen by CD4(+) and CD8(+) T lymphocytes. The presence of nontoxic concentrations of the anionic detergent cholic acid or the sulfated polymer lambda carrageenan did not inhibit recognition of immune peptide by antigen-specific T cells. However, antigen recognition by both CD4(+) and CD8(+) T lymphocytes was inhibited in the presence of the naphthalene sulfonate polymer PRO 2000. Brief (4-h) exposure of antigen-presenting cells or T cells to PRO 2000 did not result in inhibition of antigen uptake and processing by antigen-presenting cells or the ability of specific T cells to respond to antigen stimulation, suggesting that the inhibition was temporary. Binding of antibodies specific for CD18, CD8, and CD3 was impaired in the presence of PRO 2000, suggesting that the mechanism by which this microbicide inhibits T cell recognition of antigenic peptide may involve masking or internalization of surface proteins involved in T cell signaling or stabilizing T cell-antigen-presenting cell interactions. The assays described in this study represent a useful means to screen candidate topical microbicide compounds for inappropriate interactions with immune cells and may be useful for prioritization of candidate microbicide compounds.


Effectiveness of speed cameras in preventing road traffic collisions and related casualties: systematic review.
To assess whether speed cameras reduce road traffic collisions and related casualties. Systematic review. Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials, Medline, Embase, Social Science Citation Index, TRANSPORT database, ZETOC, the internet (including websites of road safety and motoring organisations), and contact with key individuals and organisations. Road traffic collisions, injuries, and deaths. Controlled trials and observational studies assessing the impact of fixed or mobile speed cameras on any of the selected outcomes. 14 observational studies met the inclusion criteria; no randomised controlled trials were found. Most studies were before-after studies without controls (n = 8). All but one of the studies showed effectiveness of cameras up to three years or less after their introduction; one study showed sustained longer term effects (4.6 years after introduction). Reductions in outcomes across studies ranged from 5% to 69% for collisions, 12% to 65% for injuries, and 17% to 71% for deaths in the immediate vicinity of camera sites. The reductions over wider geographical areas were of a similar order of magnitude. Existing research consistently shows that speed cameras are an effective intervention in reducing road traffic collisions and related casualties. The level of evidence is relatively poor, however, as most studies did not have satisfactory comparison groups or adequate control for potential confounders. Controlled introduction of speed cameras with careful data collection may offer improved evidence of their effectiveness in the future.


Is pathological gambling moderated by age?
The age of a patient is a strong moderator of both the course and the evolution of disorders/diseases. However, the effects of current age in pathological gambling (PG) have rarely been examined. The aim of this study is to explore the moderating effects of the patients' current age in relation to personality traits and clinical outcomes of PG. A total sample of 2,309 treatment-seeking patients for PG, diagnosed according to DSM-IV criteria, participated in this study and were assessed with the Diagnostic Questionnaire for Pathological Gambling according to DSM-IV criteria, the South Oaks Gambling Screen, the Symptom Checklist, the Temperament and Character Inventory-R, and other clinical and psychopathological measures. Orthogonal polynomial contrasts showed linear trends in the relationship between age and PG: the older the patient, the more comorbid health problems were visible. The presence of additional quadratic trends also suggests that age plays a significant role in moderating the possibility of existing PG problems and general psychopathology. No interaction term was found between age and sex, but it was present for age and some personality traits: self-transcendence and reward dependence (these two traits were only relevant to the level of impairment due to PG at specific ages). This study suggests that the patients' age influences psychopathological and clinical aspects associated to PG. Intervention in the earliest manifestations of this complex problem is essential in order to better address the need of successful treatment planning.


Regional models for sediment toxicity assessment.
The present study describes approaches to improve the performance of empirical models developed from a large nationwide data set to predict sediment toxicity from chemistry for regional applications. The authors developed 4 multiple chemical (PMax ) models selected from individual chemical models developed using 1) a previously published approach applied to the nationwide data set; 2) a broader array of response and explanatory variables (e.g., different normalization approaches and toxicity classifications) applied to the nationwide data set; 3) a data set from the New York/New Jersey, USA, region; and 4) both nationwide and regional data sets. The models were calibrated using the regional data set. Performance was tested using an independent data set from the same region. The performance of the final PMax model developed using the calibration process substantially improved over that of the uncalibrated PMax model developed using the nationwide data set. The improvements were achieved by selecting the best performing individual chemical models and eliminating those that performed poorly when applied together. Although the best performing PMax model included both nationwide and region-specific models, the performance of the PMax model derived using only nationwide models was nearly as good. These results suggest that calibrating nationwide models to a regional data set may be both a more efficient and effective approach for improving model performance than developing region-specific models. This article is a US Government work and is in the public domain in the USA.


Air-Track: a real-world floating environment for active sensing in head-fixed mice.
Natural behavior occurs in multiple sensory and motor modalities and in particular is dependent on sensory feedback that constantly adjusts behavior. To investigate the underlying neuronal correlates of natural behavior, it is useful to have access to state-of-the-art recording equipment (e.g., 2-photon imaging, patch recordings, etc.) that frequently requires head fixation. This limitation has been addressed with various approaches such as virtual reality/air ball or treadmill systems. However, achieving multimodal realistic behavior in these systems can be challenging. These systems are often also complex and expensive to implement. Here we present "Air-Track," an easy-to-build head-fixed behavioral environment that requires only minimal computational processing. The Air-Track is a lightweight physical maze floating on an air table that has all the properties of the "real" world, including multiple sensory modalities tightly coupled to motor actions. To test this system, we trained mice in Go/No-Go and two-alternative forced choice tasks in a plus maze. Mice chose lanes and discriminated apertures or textures by moving the Air-Track back and forth and rotating it around themselves. Mice rapidly adapted to moving the track and used visual, auditory, and tactile cues to guide them in performing the tasks. A custom-controlled camera system monitored animal location and generated data that could be used to calculate reaction times in the visual and somatosensory discrimination tasks. We conclude that the Air-Track system is ideal for eliciting natural behavior in concert with virtually any system for monitoring or manipulating brain activity.


Latest development in microalgae-biofuel production with nano-additives.
Microalgae have been experimented as a potential feedstock for biofuel generation in current era owing to its' rich energy content, inflated growth rate, inexpensive culture approaches, the notable capacity of CO2 fixation, and O2 addition to the environment. Currently, research is ongoing towards the advancement of microalgal-biofuel technologies. The nano-additive application has been appeared as a prominent innovation to meet this phenomenon. The main objective of this study was to delineate the synergistic impact of microalgal biofuel integrated with nano-additive applications. Numerous nano-additives such as nano-fibres, nano-particles, nano-tubes, nano-sheets, nano-droplets, and other nano-structures' applications have been reviewed in this study to facilitate microalgae growth to biofuel utilization. The present paper was intended to comprehensively review the nano-particles preparing techniques for microalgae cultivation and harvesting, biofuel extraction, and application of microalgae-biofuel nano-particles blends. Prospects of solid nano-additives and nano-fluid applications in the future on microalgae production, microalgae biomass conversion to biofuels as well as enhancement of biofuel combustion for revolutionary advancement in biofuel technology have been demonstrated elaborately by this review. This study also highlighted the potential biofuels from microalgae, numerous technologies, and conversion processes. Along with that, the study recounted suitability of potential microalgae candidates with an integrated design generating value-added co-products besides biofuel production. Nano-additive applications at different stages from microalgae culture to end-product utilization presented strong possibility in mercantile approach as well as positive impact on the environment along with valuable co-products generation into the near future.


Transvaginal prolapse repair with or without the addition of a midurethral sling in women with genital prolapse and stress urinary incontinence: a randomised trial.
To compare transvaginal prolapse repair combined with midurethral sling (MUS) versus prolapse repair only. Multi-centre randomised trial. Fourteen teaching hospitals in the Netherlands. Women with symptomatic stage two or greater pelvic organ prolapse (POP), and subjective or objective stress urinary incontinence (SUI) without prolapse reduction. Women were randomly assigned to undergo vaginal prolapse repair with or without MUS. Analysis was according to intention to treat. The primary outcome at 12 months' follow-up was the absence of urinary incontinence (UI) assessed with the Urogenital Distress Inventory and treatment for SUI or overactive bladder. Secondary outcomes included complications. One hundred and thirty-four women were analysed at 12 months' follow-up (63 in MUS and 71 in control group). More women in the MUS group reported the absence of UI and SUI; respectively 62% versus 30% UI (relative risk [RR] 2.09; 95% confidence interval [CI] 1.39-3.15) and 78% versus 39% SUI (RR 1.97; 95% CI 1.44-2.71). Fewer women underwent treatment for postoperative SUI in the MUS group (10% versus 37%; RR 0.26; 95% CI 0.11-0.59). In the control group, 12 women (17%) underwent MUS after prolapse surgery versus none in the MUS group. Severe complications were more common in the MUS group, but the difference was not statistically significant (16% versus 6%; RR 2.82; 95% CI 0.93-8.54). Women with prolapse and co-existing SUI are less likely to have SUI after transvaginal prolapse repair with MUS compared with prolapse repair only. However, only 17% of the women undergoing POP surgery needed additional MUS. A well-informed decision balancing risks and benefits of both strategies should be tailored to individual women.


Influences of chronic and current season grazing by collared pikas on above-ground biomass and species richness in subarctic alpine meadows.
We studied an alpine herbivory gradient established by collared pikas, a small central place foraging lagomorph, to examine the effects of multiple grazing levels on above-ground live biomass (AGB) and species richness (SR) in alpine tundra. The effects of within-season (four sampling periods), multi-season (across three summers) and longer-term dynamics (inferred from spatial location of vegetation with respect to pika haypiles) were examined. Along the grazing gradient, we found support for and against hypotheses that propose biphasic, increasing, or decreasing responses to herbivory, both in terms of AGB and SR. Our results suggest that plant-herbivore predictability is still weak. To further examine the impact of herbivory, we experimentally removed pikas using mesh exclosures placed at increasing distance from the edge of talus occupied by pikas. AGB after the second consecutive year of herbivore exclusion increased by 125% compared to control plots in highly grazed areas adjacent to talus (<1 m). In more lightly grazed sites at distances 1-6 m from talus, AGB increased by more than 40% after pikas were removed. No differences were observed in the ungrazed sites >6 m from talus. AGB was highest in meadow patches previously grazed by pikas compared to those with little grazing history, but this response was only observed after two seasons following release from herbivory. Grazed sites at distances of 1-6 m had the highest SR. These results indicate that multi-year measurements of growth are particularly relevant in ecosystems dominated by long-lived perennials in regions where productivity is low. Infrequent herbivore vacancies may provide local short-term release from pika grazing, thereby contributing to the persistence of productive, highly palatable vegetation.


miR2Gene: pattern discovery of single gene, multiple genes, and pathways by enrichment analysis of their microRNA regulators.
In recent years, a number of tools have been developed to explore microRNAs (miRNAs) by analyzing their target genes. However, a reverse problem, that is, inferring patterns of protein-coding genes through their miRNA regulators, has not been explored. As various miRNA annotation data become available, exploring gene patterns by analyzing the prior knowledge of their miRNA regulators is becoming more feasible. In this study, we developed a tool, miR2Gene, for this purpose. Various sets of miRNAs, according to prior rules such as function, associated disease, tissue specificity, family, and cluster, were integrated with miR2Gene. For given genes, miR2Gene evaluates the enrichment of the predicted miRNAs that regulate them in each miRNA set. This tool can be used for single genes, multiple genes, and KEGG pathways. For the KEGG pathway, genes with enriched miRNA sets are highlighted according to various rules. We confirmed the usefulness of miR2Gene through case studies. miR2Gene represents a novel and useful tool that integrates miRNA knowledge for protein-coding gene analysis. miR2Gene is freely available at http://cmbi.hsc.pku.edu.cn/mir2gene.


Impact of adolescent marijuana use on intelligence: Results from two longitudinal twin studies.
Marijuana is one of the most commonly used drugs in the United States, and use during adolescence--when the brain is still developing--has been proposed as a cause of poorer neurocognitive outcome. Nonetheless, research on this topic is scarce and often shows conflicting results, with some studies showing detrimental effects of marijuana use on cognitive functioning and others showing no significant long-term effects. The purpose of the present study was to examine the associations of marijuana use with changes in intellectual performance in two longitudinal studies of adolescent twins (n = 789 and n = 2,277). We used a quasiexperimental approach to adjust for participants' family background characteristics and genetic propensities, helping us to assess the causal nature of any potential associations. Standardized measures of intelligence were administered at ages 9-12 y, before marijuana involvement, and again at ages 17-20 y. Marijuana use was self-reported at the time of each cognitive assessment as well as during the intervening period. Marijuana users had lower test scores relative to nonusers and showed a significant decline in crystallized intelligence between preadolescence and late adolescence. However, there was no evidence of a dose-response relationship between frequency of use and intelligence quotient (IQ) change. Furthermore, marijuana-using twins failed to show significantly greater IQ decline relative to their abstinent siblings. Evidence from these two samples suggests that observed declines in measured IQ may not be a direct result of marijuana exposure but rather attributable to familial factors that underlie both marijuana initiation and low intellectual attainment.


SU-E-T-501: Perturbation of TG-43 Parameters of the Brachytherapy Sources under Insufficient Scattering Materials.
According to the TG-43 recommendations of American Association of Physicist in Medicine (AAPM), the dosimetry parameters of brachytherapy sources are obtained in a water phantom with full scattering conditions. However, in many actual clinical treatments the source are not surrounded with sufficient tissue in all directions to provide the full scattering condition. HDR brachytherapy of the breast or 125I eye-plaque treatment of the ocular melanoma are among the treatment sites that fits this category. In this project, the impact of insufficient phantom material surrounding the 137Cs, 192Ir, and 103Pd brachytherapy source on their TG43 dosimetric characteristics has been investigated. In this study, the effect of the insufficient tissue (referred here as missing tissues) around the brachytherapy sources on their TG-43 dosimetric parameters have been investigated using MCNP5 Monte Carlo code. The brachytherapy sources were simulated in different locations inside a cubical water phantom with the dimensions of 30*30*30 cm3 . The variation of the dosimetric parameters of the three sources (i.e. Î>, g(r), and F(r,θ)) were compared to the values from full scattering conditions (i.e. source at the center of the phantom). The results of this study indicate the variation of g(r)and 2D anisotropy function of the brachytherapy sources as a function of the missing tissue thickness. These changes increase by decreasing the energy of the photons emitted by the brachytherapy sources. These differences are mainly due to the lack of full scattering condition for the points near the phantom boundary. Unlike the published data for symmetric, but insufficient phantom material around the source, the impact of asymmetric phantom materials have been evaluated on dosimetric characteristics of the brachytherapy sources.


Structural studies of duck delta2 crystallin mutants provide insight into the role of Thr161 and the 280s loop in catalysis.
Delta crystallin, a taxon-specific crystallin present in avian eye lenses, is homologous to the urea cycle enzyme ASL (argininosuccinate lyase). Although there are two delta crystallin isoforms in duck lenses, ddeltac1 (duck delta1 crystallin) and ddeltac2 (duck delta2 crystallin), only ddeltac2 is catalytically active. Previous structural studies have suggested that residues Ser283 and His162 in the multi-subunit active site of ddeltac2/ASL are the putative catalytic acid/base, while the highly conserved, positively charged Lys289 is thought to help stabilize the carbanion intermediate. The strict conservation of a small hydroxy-containing residue (Thr or Ser) at position 161 adjacent to the putative catalytic base, as well as its proximity to the substrate in the S283A ddeltac2 enzyme-substrate complex, prompted us to investigate further the role this residue. Structures of the active T161S and inactive T161D ddeltac2 mutants, as well as T161D complexed with argininosuccinate, have been determined to 2.0 A resolution. The structures suggest that a hydroxy group is required at position 161 to help correctly position the side chain of Lys289 and the fumarate moiety of the substrate. Threonine is probably favoured over serine, because the interaction of its methyl group with Leu206 would restrict its conformational flexibility. Residues larger than Thr or Ser interfere with substrate binding, supporting previous suggestions that correct positioning of the substrate's fumarate moiety is essential for catalysis to occur. The presence of the 280s loop (i.e. a loop formed by residues 270-290) in the 'open' conformation suggests that loop closure, thought to be essential for sequestration of the substrate, may be triggered by the formation of the carbanion or aci-carboxylate intermediates, whose charge distribution more closely mimics that of the sulphate ion found in the active-site region of the inactive ddeltac1. The 280s loop in ddeltac1 is in the closed conformation.


Hyperlipidaemia and mortality among patients hospitalised with pneumonia: retrospective cohort and propensity score matched study.
To characterise the potential association of hyperlipidaemia (HLP) versus no HLP with all-cause mortality among patients hospitalised for pneumonia. Propensity score matched retrospective study. The study cohort consisted of consecutive 8553 adults hospitalised at a large academic centre with a discharge diagnosis of pneumonia from 1996 through 2015, followed until death or end of the study period, 17 August 2017. The outcome was HR for mortality at 28 days and in the long term in patients with pneumonia with concurrent HLP compared with those with no HLP. We first constructed multivariable Cox proportional regression models to estimate the association between concurrent HLP versus no HLP and mortality after pneumonia hospitalisation for the entire cohort. We then identified 1879 patients with pneumonia with concurrent HLP and propensity score matched in a 1:1 ratio to 1879 patients with no HLP to minimise the imbalance from measured covariates for further analysis. Among 8553 unmatched patients with pneumonia, concurrent HLP versus no HLP was independently associated with lower mortality at 28 days (HR 0.52, 95% CI 0.41 to 0.66) and at a median follow-up of 3.9 years (HR 0.75, 95% CI 0.70 to 0.80). The risk difference in mortality was consistent between 1879 propensity score matched pairs both at 28 days (HR 0.65, 95% CI 0.49 to 0.86) and at a median follow-up of 4 years (HR 0.88, 95% CI 0.81 to 0.96). In the subgroup of patients with clinically measured low-density lipoprotein cholesterol (LDL-C), graded inverse associations between LDL-C levels and mortality were found in both unmatched and matched cohorts. Among hospitalised patients with pneumonia, a diagnosis of HLP is protective against both short-term and long-term risk of death after adjustment for other major contributors to mortality in both unmatched and propensity score matched cohorts. These findings should be further investigated.


Non-medical prescribing versus medical prescribing for acute and chronic disease management in primary and secondary care.
A range of health workforce strategies are needed to address health service demands in low-, middle- and high-income countries. Non-medical prescribing involves nurses, pharmacists, allied health professionals, and physician assistants substituting for doctors in a prescribing role, and this is one approach to improve access to medicines. To assess clinical, patient-reported, and resource use outcomes of non-medical prescribing for managing acute and chronic health conditions in primary and secondary care settings compared with medical prescribing (usual care). We searched databases including CENTRAL, MEDLINE, Embase, and five other databases on 19 July 2016. We also searched the grey literature and handsearched bibliographies of relevant papers and publications. Randomised controlled trials (RCTs), cluster-RCTs, controlled before-and-after (CBA) studies (with at least two intervention and two control sites) and interrupted time series analysis (with at least three observations before and after the intervention) comparing: 1. non-medical prescribing versus medical prescribing in acute care; 2. non-medical prescribing versus medical prescribing in chronic care; 3. non-medical prescribing versus medical prescribing in secondary care; 4 non-medical prescribing versus medical prescribing in primary care; 5. comparisons between different non-medical prescriber groups; and 6. non-medical healthcare providers with formal prescribing training versus those without formal prescribing training. We used standard methodological procedures expected by Cochrane. Two review authors independently reviewed studies for inclusion, extracted data, and assessed study quality with discrepancies resolved by discussion. Two review authors independently assessed risk of bias for the included studies according to EPOC criteria. We undertook meta-analyses using the fixed-effect model where studies were examining the same treatment effect and to account for small sample sizes. We compared outcomes to a random-effects model where clinical or statistical heterogeneity existed. We included 46 studies (37,337 participants); non-medical prescribing was undertaken by nurses in 26 studies and pharmacists in 20 studies. In 45 studies non-medical prescribing as a component of care was compared with usual care medical prescribing. A further study compared nurse prescribing supported by guidelines with usual nurse prescribing care. No studies were found with non-medical prescribing being undertaken by other health professionals. The education requirement for non-medical prescribing varied with country and location.A meta-analysis of surrogate markers of chronic disease (systolic blood pressure, glycated haemoglobin, and low-density lipoprotein) showed positive intervention group effects. There was a moderate-certainty of evidence for studies of blood pressure at 12 months (mean difference (MD) -5.31 mmHg, 95% confidence interval (CI) -6.46 to -4.16; 12 studies, 4229 participants) and low-density lipoprotein (MD -0.21, 95% CI -0.29 to -0.14; 7 studies, 1469 participants); we downgraded the certainty of evidence from high due to considerations of serious inconsistency (considerable heterogeneity), multifaceted interventions, and variable prescribing autonomy. A high-certainty of evidence existed for comparative studies of glycated haemoglobin management at 12 months (MD -0.62, 95% CI -0.85 to -0.38; 6 studies, 775 participants). While there appeared little difference in medication adherence across studies, a meta-analysis of continuous outcome data from four studies showed an effect favouring patient adherence in the non-medical prescribing group (MD 0.15, 95% CI 0.00 to 0.30; 4 studies, 700 participants). We downgraded the certainty of evidence for adherence to moderate due to the serious risk of performance bias. While little difference was seen in patient-related adverse events between treatment groups, we downgraded the certainty of evidence to low due to indirectness, as the range of adverse events may not be related to the intervention and selective reporting failed to adequately report adverse events in many studies.Patients were generally satisfied with non-medical prescriber care (14 studies, 7514 participants). We downgraded the certainty of evidence from high to moderate due to indirectness, in that satisfaction with the prescribing component of care was only addressed in one study, and there was variability of satisfaction measures with little use of validated tools. A meta-analysis of health-related quality of life scores (SF-12 and SF-36) found a difference favouring usual care for the physical component score (MD 1.17, 95% CI 0.16 to 2.17), but not the mental component score (MD 0.58, 95% CI -0.40 to 1.55). However, the quality of life measurement may more appropriately reflect composite care rather than the prescribing component of care, and for this reason we downgraded the certainty of evidence to moderate due to indirectness of the measure of effect. A wide variety of resource use measures were reported across studies with little difference between groups for hospitalisations, emergency department visits, and outpatient visits. In the majority of studies reporting medication use, non-medical prescribers prescribed more drugs, intensified drug doses, and used a greater variety of drugs compared to usual care medical prescribers.The risk of bias across studies was generally low for selection bias (random sequence generation), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), and reporting bias (selective reporting). There was an unclear risk of selection bias (allocation concealment) and for other biases. A high risk of performance bias (blinding of participants and personnel) existed. The findings suggest that non-medical prescribers, practising with varying but high levels of prescribing autonomy, in a range of settings, were as effective as usual care medical prescribers. Non-medical prescribers can deliver comparable outcomes for systolic blood pressure, glycated haemoglobin, low-density lipoprotein, medication adherence, patient satisfaction, and health-related quality of life. It was difficult to determine the impact of non-medical prescribing compared to medical prescribing for adverse events and resource use outcomes due to the inconsistency and variability in reporting across studies. Future efforts should be directed towards more rigorous studies that can clearly identify the clinical, patient-reported, resource use, and economic outcomes of non-medical prescribing, in both high-income and low-income countries.


Intra-Capsular Versus Extra-Capsular Breast Mastopexy of Previously Augmented Breast.
The augmented breast frequently becomes ptotic by time and most of the patients may seek mastopexy. Although the rate of breast lift surgeries after breast augmentation is increasing, there are few studies regarding the nature of these procedures. Sixty patients with moderate grade ptosis and previously augmented breast by breast implants seeking breast mastopexy. Group A included 30 patients who underwent intra-capsular circum-areolar mastopexy and Group B including another 30 patients who underwent extra-capsular circum-areolar mastopexy. Follow up after complete healing was scheduled at 3, 6, and 12 months post-operative. Frontal and lateral views photography were taken each visit and objective evaluation was carried on by a plastic surgeon not involved in the surgeries. A questionnaire was performed by using the Likert scale to assess patients' satisfaction. In group A; the overall rate of complications was 17%, while in group B; the overall rate of complications was 10%. Patients of group A showed overall satisfaction of 4.53±0.69 in comparison to 3.06±0.25 in group B. In group A; objective evaluation, was excellent in 87% while in group B it was excellent in 43%. Reshaping of breast pillars mastopexy augmentation is very important to prevent bottoming-out of the breasts.


The influence of surface on the running velocities of elite and amateur orienteer athletes.
We compared the reduction in running velocities from road to off-road terrain in eight elite and eight amateur male orienteer athletes to investigate whether this factor differentiates elite from amateur athletes. On two separate days, each subject ran three 2-km time trials and three 20-m sprints "all-out" on a road, on a path, and in a forest. On a third day, the running economy and maximal aerobic power of individuals were assessed on a treadmill. The elite orienteer ran faster than the amateur on all three surfaces and at both distances, in line with their better running economy and aerobic power. In the forest, the elites ran at a slightly higher percentage of their 2-km (∼3%) and 20-m (∼4%) road velocities. Although these differences did not exhibit traditional statistical significance, magnitude-based inferences suggested likely meaningful differences, particularly during 20-m sprinting. Of course, cognitive, mental, and physical attributes other than the ability to run on different surfaces are required for excellence in orienteering (e.g., a high aerobic power). However, we suggest that athlete-specific assessment of running performance on various surfaces and distances might assist in tailoring training and identifying individual strengths and/or weaknesses in an orienteer.


Short-term Smartphone App-Based Focused Attention Meditation Diminishes Cognitive Flexibility.
Cognitive flexibility is an important aspect relevant to daily life situations, and there is an increasing public interest to optimize these functions, for example, using (brief) meditation practices. However, the underlying neurophysiological mechanisms remain poorly understood. On the basis of theoretical considerations, both improvements and deteriorations of cognitive flexibility are possible through focused attention meditation (FAM). We investigated the effect of a brief smartphone app-based FAM on task switching using EEG methods, temporal signal decomposition, and source localization techniques (standardized low-resolution electromagnetic brain tomography). The study was conducted using a crossover study design. We show that even 15 min of FAM practicing modulates memory-based task switching, on a behavioral level and a neurophysiological level. More specifically, FAM hampers response selection and conflict resolution processes and seem to reduce cognitive resources, which are necessary to rapidly adapt to changing conditions. These effects are represented in the N2 and P3 time windows and associated with ACC. It seems that FAM increases the attention to one specific aspect, which may help to focus but carries also the risk that behavior becomes too rigid. FAM thus seems to modulate both the stimulus- and response-related aspects of conflict monitoring in ACC. Motor-related processes were not affected. The results can be explained using a cognitive control dilemma framework, suggesting that particularly alterations in background monitoring may be important to consider when explaining the effects of FAM during task switching.


Development of near-infrared fluorophore (NIRF)-labeled activity-based probes for in vivo imaging of legumain.
Asparaginyl endopeptidase, or legumain, is a lysosomal cysteine protease that was originally identified in plants and later found to be involved in antigen presentation in higher eukaryotes. Legumain is also up-regulated in a number of human cancers, and recent studies suggest that it may play important functional roles in the process of tumorigenesis. However, detailed functional studies in relevant animal models of human disease have been hindered by the lack of suitably selective small molecule inhibitors and imaging reagents. Here we present the design, optimization, and in vivo application of fluorescently labeled activity-based probes (ABPs) for legumain. We demonstrate that optimized aza-peptidyl Asn epoxides are highly selective and potent inhibitors that can be readily converted into near-infrared fluorophore-labeled ABPs for whole body, noninvasive imaging applications. We show that these probes specifically label legumain in various normal tissues as well as in solid tumors when applied in vivo. Interestingly, addition of cell-penetrating peptides to the probes enhanced cellular uptake but resulted in increased cross-reactivity toward other lysosomal proteases as the result of their accumulation in lysosomes. Overall, we find that aza-peptidyl Asn ABPs are valuable new tools for the future study of legumain function in more complex models of human disease.


Trajectories of marijuana use from adolescence into adulthood: Environmental and individual correlates.
This study sought to identify trajectories of marijuana use in the Seattle Social Development Project (n = 808) sample from age 14 through 30, and to examine the extent to which individuals in these trajectories differed in their substance use problems, mental health, problem behavior, economic outcomes, and positive functioning at age 33. In addition, analyses examined between-trajectory differences in family, peer, school, neighborhood, individual, mental health, and substance use factors at key developmental points in adolescence and adulthood. Four trajectories of marijuana use were identified: nonusers (27%), adolescent-limited (21%), late-onset (20%), and chronic (32%) users. At age 33, the chronic trajectory was associated with the worst functioning overall. The late-onset group reported more substance use and sexual risk behavior than nonusers, but was otherwise not differentiated. The adolescent-limited group reported significantly lower educational and economic outcomes at age 33 than the late-onset and nonuser groups. In analyses at earlier ages, adolescent-limited and late-onset groups reported more problems in functioning during the period of escalation in use and improvement in functioning with the beginning of desistance. Implications for prevention are discussed, particularly the unique risks associated with early adolescent versus later onset of marijuana use.


Understanding the genetics of regulation of aflatoxin production and Aspergillus flavus development.
Aflatoxins are polyketide-derived, toxic, and carcinogenic secondary metabolites produced primarily by two fungal species, Aspergillus flavus and A. parasiticus, on crops such as corn, peanuts, cottonseed, and treenuts. Regulatory guidelines issued by the U.S. Food and Drug Administration (FDA) prevent sale of commodities if contamination by these toxins exceeds certain levels. The biosynthesis of these toxins has been extensively studied. About 15 stable precursors have been identified. The genes involved in encoding the proteins required for the oxidative and regulatory steps in the biosynthesis are clustered in a 70 kb portion of chromosome 3 in the A. flavus genome. With the characterization of the gene cluster, new insights into the cellular processes that govern the genes involved in aflatoxin biosynthesis have been revealed, but the signaling processes that turn on aflatoxin biosynthesis during fungal contamination of crops are still not well understood. New molecular technologies, such as gene microarray analyses, quantitative polymerase chain reaction (PCR), and chromatin immunoprecipitation are being used to understand how physiological stress, environmental and soil conditions, receptivity of the plant, and fungal virulence lead to episodic outbreaks of aflatoxin contamination in certain commercially important crops. With this fundamental understanding, we will be better able to design improved non-aflatoxigenic biocompetitive Aspergillus strains and develop inhibitors of aflatoxin production (native to affected crops or otherwise) amenable to agricultural application for enhancing host-resistance against fungal invasion or toxin production. Comparisons of aflatoxin-producing species with other fungal species that retain some of the genes required for aflatoxin formation is expected to provide insight into the evolution of the aflatoxin gene cluster, and its role in fungal physiology. Therefore, information on how and why the fungus makes the toxin will be valuable for developing an effective and lasting strategy for control of aflatoxin contamination.