General Screen Research Articles

Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi.

BackgroundCerebral malaria is one of the most severe complications of Plasmodium falciparum infection and occurs mostly in young African children. This syndrome results from a combination of high levels of parasitaemia and inflammation. Although parasite sequestration in the brain is a feature of the human syndrome, sequestering strains do not uniformly cause severe malaria, suggesting interplay with other factors. Host genetic factors such as mutations in the promoters of the cytokines IL-10 and TNF are also clearly linked to severe disease. Plasmodium chabaudi, a rodent malaria parasite, leads to mild illness in wildtype animals. However, IL-10−/− mice respond to parasite with increased levels of pro-inflammatory cytokines IFN-γ and TNF, leading to lethal disease in the absence of sequestration in the brain. These mice also exhibit cerebral symptoms including gross cerebral oedema and haemorrhage, allowing study of these critical features of disease without the influence of sequestration.MethodsThe neurological consequences of P. chabaudi infection were investigated by performing a general behavioural screen (SHIRPA). The immune cell populations found in the brain during infection were also analysed using flow cytometry and confocal microscopy.ResultsIL-10−/− mice suffer significant declines in behavioural and physical capacities during infection compared to wildtype. In addition, grip strength and pain sensitivity were affected, suggestive of neurological involvement. Several immune cell populations were identified in the perfused brain on day 7 post-infection, suggesting that they are tightly adherent to the vascular endothelium, or potentially located within the brain parenchyma. There was an increase in both inflammatory monocyte and resident macrophage (CD11bhi, CD45+, MHCII+, Ly6C+/−) numbers in IL-10−/− compared to wildtype animals. In addition, the activation state of all monocytes and microglia (CD11bint, CD45−, MHC-II+) were increased. T cells making IFN-γ were also identified in the brain, but were localized within the vasculature, and not the parenchyma.ConclusionsThese studies demonstrate exacerbated neuroinflammation concurrent with development of behavioural symptoms in P. chabaudi infection of IL-10−/− animals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1477-1) contains supplementary material, which is available to authorized users.

Novel Chemicals Identified in Pregnant Women in Northern California

Introduction: In utero exposure to multiple environmental chemicals can adversely impact health throughout the lifespan. Developing analytical techniques to rapidly characterize exposure to the full spectrum environmental chemicals present in the human body is an integral component of an “exposome” approach. Therefore we apply a new method using liquid chromatography-quadrupole time-of-flight mass spectrometry to perform a general suspects screen for the presence and co-occurrence of ~700 Environmental Organic Acids (EOAs): organic industrial chemicals with at least one dissociable proton, including phenolic compounds such as Bisphenol A; phthalate metabolites; phenolic metabolites of polybrominated diphenyl ethers and polychlorinated biphenyls; perfluorinated compounds; and phenolic and acidic pesticides and/or their predicted acidic and phenolic metabolites. Methods: We analyzed samples from 19 pregnant women in their 2nd trimester receiving care at San Francisco General Hospital, using the Agilent QTOF/MS 6550 instrument to identify ‘suspect EOAs.’ Results: We detected, on average, 100 (SD: 23) suspect EOAs in each woman (range: 56-126), including universal exposure to nine novel suspect EOAs – five phenols (e.g., 2,4-Dihydroxyphenone) and four phenolic pesticides and/or their phenolic metabolites (e.g., Dinoterb) – and two previously biomonitored suspect EOAs ((Mono-n-butyl phthalate (MnBP) and Perfluoroundecanoic acid (PFUA)). Some suspect EOAs that we detected in all participants who smoked last year were detected in only 60% of their counterparts. We detected in all Black participants ~17 suspect EOAs that had <60% detection frequency in White and Latina participants. Conclusion: Non-targeted analysis provides a viable method to screen for a broad spectrum of chemicals and help identify ubiquitously present and thus priority chemicals for targeted method development.

Phos-tag SDS-PAGE resolves agonist- and isoform-specific activation patterns for PKD2 and PKD3 in cardiomyocytes and cardiac fibroblasts

Protein kinase D (PKD) consists of a family of three structurally related enzymes that are co-expressed in the heart and have important roles in many biological responses. PKD1 is activated by pro-hypertrophic stimuli and has been implicated in adverse cardiac remodeling. Efforts to define the cardiac actions of PKD2 and PKD3 have been less successful at least in part because conventional methods provide a general screen for PKD activation but are poorly suited to resolve activation patterns for PKD2 or PKD3. This study uses Phos-tag SDS-PAGE, a method that exaggerates phosphorylation-dependent mobility shifts, to overcome this technical limitation. Phos-tag SDS-PAGE resolves PKD1 as distinct molecular species (indicative of pools of enzyme with distinct phosphorylation profiles) in unstimulated cardiac fibroblasts and cardiomyocytes; as a result, attempts to track PKD1 mobility shifts that result from agonist activation were only moderately successful. In contrast, PKD2 and PKD3 are recovered from resting cardiac fibroblasts and cardiomyocytes as single molecular species; both enzymes display robust mobility shifts in Phos-tag SDS-PAGE in response to treatment with sphingosine-1-phosphate, thrombin, PDGF, or H2O2. Studies with GF109203X implicate protein kinase C activity in the stimulus-dependent pathways that activate PKD2/PKD3 in both cardiac fibroblasts and cardiomyocytes. Studies with C3 toxin identify a novel role for Rho in the sphingosine-1-phosphate and thrombin receptor-dependent pathways that lead to the phosphorylation of PKD2/3 and the downstream substrate CREB in cardiomyocytes. In conclusion, Phos-tag SDS-PAGE provides a general screen for stimulus-specific changes in PKD2 and PKD3 phosphorylation and exposes a novel role for these enzymes in specific stress-dependent pathways that influence cardiac remodeling.

Laterality of radiographic osteoarthritis of the knee

ABSTRACTThere are few reports of the laterality in radiological knee osteoarthritis (ROA). This study aimed to evaluate laterality in terms of the minimum joint space width (mJSW) and osteophyte areas (OFs) in a cross-sectorial general population screen and elucidate the association between laterality and risk of osteoarthritis. We enrolled 330 participants (mean age 64.6 years) and examined the presence of ROA (Kellgren–Lawrence grade ≧ 2) laterality in terms of the mJSW and OF on the medial tibia using auto-measuring software. Moreover, we examined the association between laterality and leg dominance. The right and left medial mJSWs were 4.02 ± 0.98 mm and 4.05 ± 1.01 mm, respectively, showing no laterality; the laterals were also similar. The participants who had osteophytes ≥1 mm2 in the right, left, and bilateral knees were 15, 37, and 57 respectively, with osteophytes being significantly more common in the left knee. The OF was significantly larger in the left knee. Conversely, the medial and lateral mJSWs and OF did not differ according to leg dominance. The prevalence of ROA was higher and the OF was more pronounced in the left knee. However, the mJSW showed no laterality. Additionally, the mJSW and OF showed no differences according to leg dominance.

Mental Health Screening in Juvenile Justice Settings: Evaluating the Utility of the Massachusetts Youth Screening Instrument, Version 2

Allocating limited mental health resources is a challenge for juvenile justice facilities. We evaluated the clinical utility of the Massachusetts Youth Screening Instrument, Version 2 (MAYSI-2)—an instrument designed to aid in this process—in three subsamples of justice-involved youth (ages 14-17): detained girls ( n = 69), detained boys ( n = 130), and incarcerated boys ( n = 373). For perspective, we compared its performance (in the incarcerated subsample) to that of the Youth Self-Report (YSR), a more widely-used screen. The MAYSI-2 subscales were moderately useful for detecting relevant diagnoses, and differences were observed across samples. However, as a general mental health screen, the MAYSI-2 performed well (and comparably to the YSR), correctly classifying 66% to 75% of youth. When used to differentiate youth with any and without any disorder, both instruments were effective. Given the MAYSI-2’s practical advantages over the YSR (lower cost, easier administration), it may be a better option for juvenile facilities.

Evaluation of Delayed Puberty: What Diagnostic Tests Should be Done in the Seemingly Otherwise Well Adolescent?

Abstract BACKGROUND: Delayed puberty (DP) is defined as the lack of puberty by an age that is 2-2.5 standard deviations beyond the population mean. Although it generally represents a normal variant in pubertal timing, DP can be the initial presentation of a serious underlying disorder and can be a source of significant anxiety for patients and their parents. Despite its clinical importance, the initial diagnostic approach to this condition is variable and may include tests that are unnecessary and costly. OBJECTIVES: To review the current recommendations regarding the initial evaluation of DP in the seemingly otherwise well adolescent and provide a rationale for revisiting these recommendations using data from our centre. DESIGN/METHODS: We reviewed clinical and laboratory data of patients seen for DP in the Endocrinology Clinic at the Hospital for Sick Children through retrospective chart review of patients seen between 08/2012 and 12/2013 and prospective chart review of those seen between 01/2014 and 07/2014. RESULTS: 519 charts were reviewed retrospectively and 58 met inclusion criteria; 6 additional patients were identified prospectively (n=64; 40 male, 24 female). Among the patients who were previously healthy, 70% had constitutional delay of growth and puberty, 18% had functional hypogo-nadotropic hypogonadism (FHH), 7% had permanent hypogonadotropic hypogonadism and 4% had hypergonadropic hypogonadism. Wide inter-practitioner variability in the number of diagnostic tests ordered, ranging from 3 to 27, was observed. The mean number of diagnostic tests ordered at the patient’s initial visit was 16 with a median of 17. Diagnostic tests ordered to identify FHH in the absence of signs or symptoms of an underlying disorder, including thyroid function testing, celiac antibodies and general screens for systemic illness were not helpful. CONCLUSION: We found wide variability in the number of diagnostic tests ordered during the initial work-up of DP. Furthermore, the majority of tests ordered had a low diagnostic yield in patients with low pre-test probability. We propose that initial diagnostic testing in an otherwise healthy adolescent with DP should only consist of gonadotropins and close clinical monitoring. A bone age, while non-diagnostic, is useful for height prediction.

Non-Verbal Episodic Memory Deficits in Primary Progressive Aphasias are Highly Predictive of Underlying Amyloid Pathology.

Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer's disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases.

Injury prevention strategies, coach compliance and player adherence of 33 of the UEFA Elite Club Injury Study teams: a survey of teams’ head medical officers

Purpose(1) To quantify current practice at the most elite level of professional club football in Europe with regard to injury prevention strategy; (2) to describe player adherence and coach compliance...

Effects of pentobarbital, isoflurane, or medetomidine–midazolam–butorphanol anesthesia on bronchoalveolar lavage fluid and blood chemistry in rats

Bronchoalveolar lavage fluid (BALF) is commonly examined for pulmonary toxicity in animal studies. Two common means of anesthesia before euthanasia and bronchoalveolar lavage in rats are intraperitoneal injection of pentobarbital and inhalation of isoflurane. Medetomidine-midazolam-butorphanol is an alternative anesthesia to pentobarbital for animal welfare; however, the effect of this combination on BALF and blood chemistry is unknown. Here, we compared the effects of anesthesia by intraperitoneal injection of pentobarbital or one of two combinations of medetomidine-midazolam-butorphanol (dose, 0.375-2.0-2.5 or 0.15-2.0-2.5 mg/kg) or by inhalation of isoflurane on BALF and blood chemistry in rats with or without pulmonary inflammation. In BALF, we determined total protein, albumin, lactate dehydrogenase, total cell count and neutrophil count. In serum, we conducted a general chemistry screen. After anesthesia with pentobarbital or isoflurane, there were no significant differences between any of the BALF or blood chemistry parameters with or without inflammation. After anesthesia with either of the combinations of medetomidine-midazolam-butorphanol, lactate dehydrogenase, total cell count, neutrophil count, and almost all of the blood chemistry parameters were comparable with those observed after pentobarbital or isoflurane; however, BALF albumin and serum glucose were significantly increased in rats without inflammation. After the combination of low-dose medetomidine in rats with inflammation, BALF parameters were comparable with those observed after pentobarbital or isoflurane. Our results show that, of the anesthetics examined, inhalation of isoflurane is the most appropriate means of anesthesia when examining BALF or serum for toxicity studies in rats.

FMS Scores Change With Performers' Knowledge of the Grading Criteria-Are General Whole-Body Movement Screens Capturing "Dysfunction"?

Deficits in joint mobility and stability could certainly impact individuals' Functional Movement Screen (FMS) scores; however, it is also plausible that the movement patterns observed are influenced by the performers' knowledge of the grading criteria. Twenty-one firefighters volunteered to participate, and their FMS scores were graded before and immediately after receiving knowledge of the movement patterns required to achieve a perfect score on the FMS. Standardized verbal instructions were used to administer both screens, and the participants were not provided with any coaching or feedback. Time-synchronized sagittal and frontal plane videos were used to grade the FMS. The firefighters significantly (p < 0.001) improved their FMS scores from 14.1 (1.8) to 16.7 (1.9) when provided with knowledge pertaining to the specific grading criteria. Significant improvements (p < 0.05) were also noted in the deep squat (1.4 [0.7]-2.0 [0.6]), hurdle step (2.1 [0.4]-2.4 [0.5]), in-line lunge (2.1 [0.4]-2.7 [0.5]), and shoulder mobility (1.8 [0.8]-2.4 [0.7]) tests. Because a knowledge of a task's grading criteria can alter a general whole-body movement screen score, FMS or otherwise, observed changes may not solely reflect "dysfunction." The instant that individuals are provided with coaching and feedback regarding their performance on a particular task, the task may lose its utility to evaluate the transfer of training or predict musculoskeletal injury risk.

How should a district general hospital immunology service screen for anti-nuclear antibodies? An 'in-the-field' audit.

Anti-nuclear antibody (ANA) testing assists in the diagnosis of several immune-mediated disorders. The gold standard method for detection of these antibodies is by indirect immunofluorescence testing on human epidermoid laryngeal carcinoma (HEp-2) cells. However, many laboratories test for these antibodies using solid-phase assays such as enzyme-linked immunosorbent assay (ELISA), which allows for higher throughput testing at reduced cost. In this study, we have audited the performance of a previously established ELISA assay to screen for ANA, making comparison with the gold standard HEp-2 immunofluorescence test. A prospective and unselected sample of 89 consecutive ANA test requests by consultant rheumatologists were evaluated in parallel over a period of 10 months using both tests. ELISA and HEp-2 screening assays yielded 40 (45%) and 72 (81%) positive test results, respectively, demonstrating lack of concordance between test methods. Using standard and clinical samples, it was demonstrated that the ELISA method did not detect several ANA with nucleolar, homogeneous and speckled immunofluorescence patterns. None of these ELISA(NEG) HEp-2(POS) ANA were reactive with a panel of six extractable nuclear antigens or with double-stranded DNA. Nonetheless, 13 of these samples (15%) originated from patients with recognized ANA-associated disease (n = 7) or Raynaud's phenomenon (n = 6). We conclude that ELISA screening may fail to detect clinically relevant ANA that lack defined specificity for antigen.

Spatial distribution of 5-hydroxymethyl cytosine in rat brain and temporal distribution in striatum.

Recently, 5-hydroxymethyl cytosine (5hmC) was identified in higher organisms as a novel epigenetic modification factor, and was found to be substantially enriched in the central nervous system relative to many other tissues and cell types. Additionally, epigenetic modifications are markedly involved in many neurological disorders. However, the precise role of 5hmC in the brain and neurological diseases remains elusive. To reveal its functional role, a general screen of its spatial and temporal distribution was proposed as being a reasonable starting investigation. Here, we found that 5hmC was widely distributed in the cerebral cortex, striatum, hippocampus, cerebellum, and the brain stem. At the cellular level, 5hmC was widely expressed in neurons and astrocytes even probably the majority of glial cells. Further, the content of 5hmC in different brain regions was inconsistent. Moreover, the pattern of 5hmC in the regions of the whole rat brain was highly susceptible to age-associated modifications. We also found similar phenomena in the striatum, which had not been previously studied. Also, unlike other brain regions, for example in the cerebellum and granulosa cells, 5hmC also appeared to display specific expression in these tissues. However, we didn't obtain the expected result that 5hmC will be increased in 6-hydroxydopamine-induced models of Parkinson's disease with regard the preliminary exploration of 5hmC in these models. Our results suggest that in rats and other mammals, 5hmC likely plays an important role in the brain and is associated with neural development and aging in different areas of the brain.

Global Stability of an Age Structured SEIRS Epidemic Model with Screening

We formulate an age structured SEIRS model with general screen function and contact rate. A condition is obtained, and under which the endemic equilibrium is locally stable. By constructing suitable Lyapunov function, the global stability of the endemic equilibrium is discussed.

PSORIATIC ARTHRITIS: CLASSIFICATION, CLINICAL PRESENTATION, DIAGNOSIS, TREATMENT

The lecture gives basic information about psoriatic arthritis (PsA), a chronic inflammatory disease of the joints, spine, and enthesises from a group of spondyloarthritis. It describes the epidemiology of the disease and considers current ideas on its pathogenesis and factors influencing the development of PsA in psoriatic patients. The classification and clinical forms of PsA are presented. The major clinical manifestations of the disease are indicated to include peripheral arthritis, enthesitis, dactylitis, and spondylitis. The diagnosis of the disease is noted to be established on the basis of its detected typical clinical and radiological signs, by applying the CASPAR criteria. A dermatologist, rheumatologist, and general practitioner screen PsA, by actively detecting complaints, characteristic clinical and radiological signs of damage to the joints, and/or spine, and/or enthesises and by using screening questionnaires. There are data that patients with PsA are observed to be at higher risk for a number of diseases type 2 diabetes mellitus hypertension, coronary heart disease, obesity, metabolic syndrome, inflammatory bowel diseases, etc. The aim of current pharmacotherapy for PsA is to achieve remission or minimal activity of clinical manifestations of the disease, to delay or prevent its X-ray progression, to increase survival, to improve quality of life in patients, and to reduce the risk of comorbidities. The paper considers groups of medicines used to treat the disease, among other issues, information about biological agents (BA) registered in the Russian Federation for the treatment of PsA. Most patients are mentioned to show a good response to this therapy option just 3–6 months after treatment initiation; however, some of them develop primary inefficiency. In this case, switching one BA to another is recommended. Some patients using a BA develop secondary treatment inefficiency, which is firstly due to the appearance of neutralizing antibodies and to the decrease of blood drug concentrations. Concurrent methotrexate therapy is noted to improve adherence to BA therapy in patients with PsA.

Comparison of Kinyoun's acid-fast and immunofluorescent methods detected an unprecedented occurrence of Cryptosporidium in the Eastern Region of Saudi Arabia

Abstract Objectives The aim of this study was to compare the diagnostic sensitivity and specificity of the modified Kinyoun's acid-fast test used widely in Saudi Arabia compared to the direct immunofluorscent assay (DFA) for monitoring the occurrence of Cryptosporidium spp. Methods We compared the conventional, modified Kinyoun's acid-fast with the Merifluor direct immunofluorscent assay for the detection of Cryptosporidium oocysts in 100 stool samples, among patients who reported to King Fahad Military Medical Complex during April–May, 2012. Results The modified Kinyoun's method and the DFA revealed 49 and 66 Cryptosporidium oocyst positives, respectively. Sensitivity and specificity of acid-fast when compared to DFA, were 66.67% (95% CI: 53.99%–77.79%) and 88.24% (95% CI: 72.53%–96.63%), respectively, (Kappa = 0.487 and the 95% confidence interval was 0.328–0.645). The positive and negative predictive values of the same method were 91.67% (95% CI: 80.00%–97.63% and 57.69% (95% CI: 43.21%–71.27%), respectively. Conclusion The DFA was found to be simple to perform and has been demonstrated to have a higher sensitivity than traditional staining procedures. The current positivity rate of 66% of Cryptosporidium in this study is higher than indicated before by several studies. This disease remains underdiagnosed in current routine laboratory procedures. It is recommended that tests for Cryptosporidium be done as part of a general diarrhea screen during standard stool tests in diagnostic laboratories.

Editorial: mining for pharmacophores in phenotypic screens.

Let's consider the growing popularity of phenotypic screens within the drug development community. Biochemical assays once dominated the field of high throughput chemical screening, but phenotypic experiments are more adept at modeling real physiological behavior, and can simultaneously mimic drug delivery factors including cell membrane permeability, intracellular localization, and aspects of transport and metabolism. Efficiency and cost of phenotypic screens have improved substantially over the years. For all of these reasons, the technology is well suited to fostering lead optimization. The technology has disadvantages, however, in that data complexity hinders de novo SAR rationalization. For preliminary screens over diverse chemotypes, the simpler biochemical construct affords a good platform for classifying hits according to target-specific modulation, thus facilitating systematic pharmacophore perception. With phenotypic screens, activity trends across different chemotypes may actually reflect modulation of different biochemical targets or via distinct interaction modes. Even within the same chemotype family, pharmacophore perception may be occluded by imprecise partitioning of observed bioactivity measurements between fundamental biochemical modulation versus variation across ADME-like factors. So the question arises: can phenotypic screens ultimately support systematic SAR-driven pharmacophore perception and thus fully supplant biochemical screens? The answer may be computational in nature: given a large, accurate phenotypic data set, one should theoretically be able to sort through the various influences to distill a reliable chemotype-specific SAR that distinguishes targetspecific trends from deliverability issues. This can be achieved via data mining. Unfortunately, many people who realize that data mining is designed for such challenges may be missing background insight that is key to exploiting such methods. Most often overlooked is the fact that excellent calculations will rarely rescue weak data. Grasping pharmacophore effects from a screening study requires data sets that are strategically sensitive to variations in molecular effects that dictate physiology. In order for a given chemical to exert specific biochemical activity, it must have the right solubility profile to be available to those biomolecules that must collectively admit, transport and bind the modulator in order to effect applicable bioactivity. Ligand solubility is determined by chemical substructures. Furthermore, every relevant intermolecular interaction is directly influenced by ligand chemical composition. Thus, if one knows which chemical substructures balance appropriate solubility with the interactions required to reach and bind the biomolecular target, one should be able to predict ligand activity. This is the essence of rational drug design and is, furthermore, the type of insight that careful mining of a well crafted data set should yield. A thorough discourse on 'careful' data mining, would take up much more than the space available to an editorial like this, but of more immediate interest to non-informaticians who design chemical screens would be a quick synopsis of what well crafted data sets might look like. To a significant extent, the data set will depend on whether one is trying to refine one's knowledge of the target specific SAR in a system, or if one is searching de novo for promising new chemotypes with activity toward a given phenotype. Ultimately, the strategy lies in giving the informatician the right spread of data to partition the global bioactivity measurement into contributing factors. In the simpler case where a chemotype family of interest has already been identified, the set of compounds screened should focus on chemicals with the desired core scaffold (or close variants thereof) so that subsequent data analysis will be emphasize SAR within that family and avoid informational contamination from other mechanisms of action. However, it can help to retain a small population of compounds derived from chemical families that likely act via distinct mechanisms; this enables computational differentiation not only between chemical properties that influence whether a given compound is active, but also perception of attributes that push modulators toward one mechanism over another. Secondly, although it may seem counter-intuitive to populate your screen with compounds known to have marginal solubility, membrane permeability or transport efficacy, a data set that includes them will also produce analysis that can distinguish molecular properties that favor target-specific interactions, versus those that amplify bioactivity simply by ensuring greater compound availability to the target. For speculative preliminary studies, systematic screening set selection reflects other considerations. Unlike targeted screening, the useful information from general preliminary screens is enhanced by embracing broad chemical functionality to reduce the number of potentially relevant chemotypes that are overlooked. Preliminary screens should also rigorously eschew compounds with poor ADME properties, since at this early stage there is little benefit in degrading chemotype-specific assessments with inactivity arising from factors other than target-compatibility. Resulting SAR analysis may blend factors that reflect target-specific effects with deliverability, but at least will lay a solid foundation for subsequent targeted lead discovery and refinement studies.

Effects of proarrhythmic drugs on relaxation time and beating pattern in rat engineered heart tissue.

The assessment of proarrhythmic risks of drugs remains challenging. To evaluate the suitability of rat engineered heart tissue (EHT) for detecting proarrhythmic effects. We monitored drug effects on spontaneous contractile activity and, in selected cases, on action potentials (sharp microelectrode) and Ca2+ transients (Fura-2) and contraction under electrical pacing. The Ito-blocker inhibitor 4-aminopyridine increased action potential duration and T2 and caused aftercontractions, which were abolished by inhibitors of ryanodine receptors (RyR2; JTV-519) or sodium calcium exchanger (NCX; SEA0400). 77 Drugs were then tested at 1-10-100× free therapeutic plasma concentrations (FTPC): Inhibitors of IKr, IKs, Ito, antiarrhythmics (8), drugs withdrawn from market for torsades des pointes arrhythmias (TdP, 5), drugs with measurable (7) or isolated TdP incidence (13), drugs considered safe (14), 28 new chemical entities (NCE). Inhibitors of IKr or IKs had no effect alone, but substantially prolonged relaxation time (T2) when combined at high concentration. 15/33 drugs associated with TdP and 6/14 drugs considered non-torsadogenic (cibenzoline, diltiazem, ebastine, ketoconazole, moxifloxacin, and phenytoin) induced concentration-dependent T2 prolongations (10-100× FTPC). Bepridil, desipramine, imipramine, thioridazine, and erythromycin induced irregular beating. Three NCE prolonged T2, one reduced force. Drugs inhibiting repolarization prolong relaxation in rat EHTs and cause aftercontractions involving RyR2 and NCX. Insensitivity to IKr inhibitors makes rat EHTs unsuitable as general proarrhythmia screen, but favors detection of effects on Ito, IKs + Ito or IKs + IKr. Screening a large panel of drugs suggests that effects on these currents, in addition to IKr, are more common than anticipated.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-014-0436-7) contains supplementary material, which is available to authorized users.

The Stroke Assessment of Fall Risk (SAFR): predictive validity in inpatient stroke rehabilitation

Objective: To evaluate relative accuracy of a newly developed Stroke Assessment of Fall Risk (SAFR) for classifying fallers and non-fallers, compared with a health system fall risk screening tool, the Fall Harm Risk Screen. Design and setting: Prospective quality improvement study conducted at an inpatient stroke rehabilitation unit at a large urban university hospital. Participants: Patients admitted for inpatient stroke rehabilitation (N = 419) with imaging or clinical evidence of ischemic or hemorrhagic stroke, between 1 August 2009 and 31 July 2010. Interventions: Not applicable. Main outcome measure(s): Sensitivity, specificity, and area under the curve for Receiver Operating Characteristic Curves of both scales’ classifications, based on fall risk score completed upon admission to inpatient stroke rehabilitation. Results: A total of 68 (16%) participants fell at least once. The SAFR was significantly more accurate than the Fall Harm Risk Screen (p < 0.001), with area under the curve of 0.73, positive predictive value of 0.29, and negative predictive value of 0.94. For the Fall Harm Risk Screen, area under the curve was 0.56, positive predictive value was 0.19, and negative predictive value was 0.86. Sensitivity and specificity of the SAFR (0.78 and 0.63, respectively) was higher than the Fall Harm Risk Screen (0.57 and 0.48, respectively). Conclusions: An evidence-derived, population-specific fall risk assessment may more accurately predict fallers than a general fall risk screen for stroke rehabilitation patients. While the SAFR improves upon the accuracy of a general assessment tool, additional refinement may be warranted.

Carotid Artery FDG Uptake May Serve as a Biomarker for Cardiovascular Risk Stratification in Asymptomatic Adults.

We investigated the relation between carotid artery FDG uptake and cardiovascular risk based on the Framingham risk score (FRS) and evaluated the possible role of FDG uptake in terms of risk stratification of asymptomatic adults. We evaluated 290 adults who underwent FDG PET/CT as part of general health screens. We calculated target-to-background ratios, corrected for pre-scan blood glucose levels, and obtained "TBRglu" values for both common carotid arteries. The FRS and the presence/absence of metabolic syndrome were recorded for each subject. Relationships among TBRglu values, metabolic syndrome status, and clinical parameters were assessed. Carotid artery FDG uptake was significantly associated with clinical risk factors. Stepwise multiple regression analysis revealed that triglyceride levels, diabetes, and metabolic syndrome were independent determinants of high TBRglu. Of subjects with metabolic syndrome, those exhibiting high carotid artery FDG uptake had significantly higher levels of high sensitivity C-reactive protein (hsCRP). In subjects who did not have metabolic syndrome, FRSs were significantly elevated in those exhibiting high carotid artery FDG uptake compared to those with low uptake (13.1 ± 7.0 vs. 8.2 ± 7.4), as was also true of subjects with the syndrome (21.8 ± 16.0 vs. 13.5 ± 11.9). High carotid FDG uptake is significantly associated with clinical risk factors and a greater FRS. Of subjects with metabolic syndrome, those with high carotid uptake had significantly higher hsCRP concentrations and FRSs. Therefore, carotid artery FDG activity may serve as a possible biomarker allowing cardiovascular risk stratification of asymptomatic populations.

熟悉性和自我相关性对网名识别的影响

采用视觉搜索范式，从熟悉性和自我相关性两个角度对自己网名存在加工优势的原因进行探讨。实验一以网名的使用频率分组，通过比较两组被试对自己网名和名人名字或对照网名的搜索成绩，来探究熟悉性和自我相关性对网名识别加工的影响模式。结果显示两组被试对自己网名的搜索成绩均显著高于其他刺激材料，高/低频组被试对自己网名的搜索成绩差异不显著。实验二、实验三采用被试内设计，分别以名人名字、对照网名和自己高、低频网名为材料，进一步探究了熟悉性在自己网名搜索中的作用。结果发现，被试搜索名人名字的成绩显著高于对照网名，但对自己使用频率不同的网名的搜索成绩无显著差异。以上研究表明自我相关性是自己网名存在加工优势重要原因，熟悉性只对视觉搜索本身有作用，而对网名识别任务没有实质影响。 The present study used a series of visual search experiments to explore the reason of the cognitive priority of screen names and mainly focused on the possible effects of the familiarity and self-relevance. In experiment 1, the participants were divided into two groups (high-frequency vs. low-frequency) according to the usage frequency of their own screen names. The results showed that the performances for own screen-name in both groups were significantly better than any other materials, while no significant difference was found between the high-frequency and low-fre- quency group. Experiment 2 and 3 were one-way within-subjects design. Experiment 2 aimed to explore the effect of familiarity on the visual search task by comparing the performance of famous names and that of general screen names. Experiment 3 explored the effect of familiarity on the screen name recognition by directly comparing the visual search performance between the two different usage frequency screen names. Results showed that famous names were detected more accurately and quickly than general screen names, while there were no significant differences between the two screen names. In conclusion, the present research confirmed the cognitive priority of self-related screen names, and found the vital role of self-relevance on the visual search of screen names. Moreover it also suggested that the familiarity might not be the key factor for the processing priority although it had an effect on the visual search.