title stringlengths 0 901 | abstract stringlengths 3 9.89k | PMID int64 22 25.3M | embedding listlengths 768 768 |
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ENAM mutations with incomplete penetrance. | Amelogenesis imperfecta (AI) is a genetic disease affecting tooth enamel formation. AI can be an isolated entity or a phenotype of syndromes. To date, more than 10 genes have been associated with various forms of AI. We have identified 2 unrelated Turkish families with hypoplastic AI and performed mutational analysis. Whole-exome sequencing identified 2 novel heterozygous nonsense mutations in the ENAM gene (c.454G>T p.Glu152* in family 1, c.358C>T p.Gln120* in family 2) in the probands. Affected individuals were heterozygous for the mutation in each family. Segregation analysis within each family revealed individuals with incomplete penetrance or extremely mild enamel phenotype, in spite of having the same mutation with the other affected individuals. We believe that these findings will broaden our understanding of the clinical phenotype of AI caused by ENAM mutations. | 25,143,514 | [
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How much does Disease Activity Score in 28 joints ESR and CRP calculations underestimate disease activity compared with the Simplified Disease Activity Index? | Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) is used instead of erythrocyte sedimentation rate (DAS28-ESR) to assess rheumatoid arthritis disease activity; however, values for remission and low disease activity (LDA) for DAS28-CRP have not been validated. American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) guidelines suggest remission should be calculated by Simplified Disease Activity Index (SDAI) rather than DAS28-ESR. We examined values of remission and LDA of DAS28-CRP that correspond to the respective cut-off points for DAS28-ESR and SDAI from five clinical trials. DAS28-CRP cut-offs that best correspond to DAS28-ESR remission <2.6 and LDA ≤3.2 were obtained by cumulative distribution plots, receiver operating curves and maximum concordance and averaged for each approach, treatment group and study. Level of agreement between DAS28-CRP and DAS28-ESR remission and LDA cut-offs was compared against each other and versus SDAI remission ≤3.3 and LDA ≤11. Percentage of patients who achieved remission and LDA by DAS28-ESR cut-offs was greater for DAS28-CRP versus DAS28-ESR regardless of patient population or treatment group. Discordance between CRP and ESR cut-offs ranged from 4%-26% and 8%-23% for remission and LDA, respectively, and 19%-40% and 6%-11% for DAS28-CRP versus SDAI, respectively. Estimated (range) remission and LDA thresholds were 2.4 (2.2-2.6) and 2.9 (2.6-3.3), 1.9 (1.6-2.2) and 3.1 (3.1-3.3) and 2.2 (1.1-2.9) and 3.6 (3.4-4.0) for DAS28-CRP versus DAS28-ESR, DAS28-CRP versus SDAI and DAS28-ESR versus SDAI, respectively. DAS28-CRP underestimates disease activity when using cut-off points validated for DAS28-ESR; therefore, DAS28-ESR cut-off values should not be applied to DAS28-CRP. Although DAS28-CRP and DAS28-ESR cut-offs for LDA ≤3.2 correspond to SDAI LDA, neither corresponds well to SDAI remission. | 25,143,522 | [
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Mechanism by which a LINE protein recognizes its 3' tail RNA. | LINEs mobilize their own copies via retrotransposition. LINEs can be divided into two types. One is a stringent type, which constitutes a majority of LINEs. The other is a relaxed type. To elucidate the molecular mechanism of retrotransposition, we used here two different zebrafish LINEs belonging to the stringent type. By using retrotransposition assays, we demonstrated that proteins (ORF2) encoded by an individual LINE recognize the cognate 3' tail sequence of the LINE RNA strictly. By conducting in vitro binding assays with a variety of ORF2 proteins, we demonstrated that the region between the endonuclease and reverse transcriptase domains in ORF2 is the site at which the proteins bind the stem-loop structure of the 3' tail RNA, showing that the strict recognition of the stem-loop structure by the cognate ORF2 protein is an important step in retrotransposition. This recognition can be bipartite, involving the general recognition of the stem by cTBR (conserved tail-binding region) of ORF2 and the specific recognition of the loop by vTBR (variable tail-binding region). This is the first report that clearly characterized the RNA-binding region in ORF2, providing the generality for the recognition mechanism of the RNA tail by the ORF2 protein encoded by LINEs. | 25,143,533 | [
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Retinoid acid-related orphan receptor γ, RORγ, participates in diurnal transcriptional regulation of lipid metabolic genes. | The hepatic circadian clock plays a pivotal role in regulating major aspects of energy homeostasis and lipid metabolism. In this study, we show that RORγ robustly regulates the rhythmic expression of several lipid metabolic genes, including the insulin-induced gene 2a, Insig2a, elongation of very long chain fatty acids-like 3, Elovl3 and sterol 12α-hydroxylase, Cyp8b1, by enhancing their expression at ZT20-4. The time-dependent increase in their expression correlates with the rhythmic expression pattern of RORγ. The enhanced recruitment of RORγ to ROREs in their promoter region, increased histone acetylation, and reporter and mutation analysis support the concept that RORγ regulates the transcription of several lipid metabolic genes directly by binding ROREs in their promoter regulatory region. Consistent with the disrupted expression of a number of lipid metabolic genes, loss of RORγ reduced the level of several lipids in liver and blood in a ZT-preferred manner. Particularly the whole-body bile acid pool size was considerably reduced in RORγ(-/-) mice in part through its regulation of several Cyp genes. Similar observations were made in liver-specific RORγ-deficient mice. Altogether, our study indicates that RORγ functions as an important link between the circadian clock and the transcriptional regulation of several metabolic genes. | 25,143,535 | [
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Differential modulation of descending signals from the reticulospinal system during reaching and locomotion. | We tested the hypothesis that the same spinal interneuronal pathways are activated by the reticulospinal system during locomotion and reaching. If such were the case, we expected that microstimulation within the pontomedullary reticular formation (PMRF) would evoke qualitatively similar responses in muscles active during both behaviors. To test this, we stimulated in 47 sites within the PMRF during both tasks. Stimulation during locomotion always produced a strongly phase-dependent, bilateral pattern of activity in which activity in muscles was generally facilitated or suppressed during one phase of activity (swing or stance) and was unaffected in the other. During reaching, stimulation generally activated the same muscles as during locomotion, although the modulation of the magnitude of the evoked responses was less limb dependent than during locomotion. An exception was found for some forelimb flexor muscles that were strongly facilitated by stimulation during the swing phase of locomotion but were not influenced by stimulation during the transport phase of the reach. We suggest that during locomotion the activity in interneuronal pathways mediating signals from the reticulospinal system is subject to strong modulation by the central pattern generator for locomotion. During reach, we suggest that, for most muscles, the same spinal interneuronal pathways are used to modify muscle activity but are not as strongly gated according to limb use as during locomotion. Finally, we propose that the command for movement during discrete voluntary movements suppresses the influence of the reticulospinal system on selected forelimb flexor muscles, possibly to enhance fractionated control of movement. | 25,143,539 | [
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The organization and dynamics of corticostriatal pathways link the medial orbitofrontal cortex to future behavioral responses. | Accurately making a decision in the face of incongruent options increases the efficiency of making similar congruency decisions in the future. Contextual factors like reward can modulate this adaptive process, suggesting that networks associated with monitoring previous success and failure outcomes might contribute to this form of behavioral updating. To evaluate this possibility, a group of healthy adults (n = 30) were tested with functional MRI (fMRI) while they performed a color-word Stroop task. In a conflict-related region of the medial orbitofrontal cortex (mOFC), stronger BOLD responses predicted faster response times (RTs) on the next trial. More importantly, the degree of behavioral adaptation of RTs was correlated with the magnitude of mOFC-RT associations on the previous trial, but only after accounting for network-level interactions with prefrontal and striatal regions. This suggests that congruency sequencing effects may rely on interactions between distributed corticostriatal circuits. This possibility was evaluated by measuring the convergence of white matter projections from frontal areas into the striatum with diffusion-weighted imaging. In these pathways, greater convergence of corticostriatal projections correlated with stronger functional mOFC-RT associations that, in turn, provided an indirect pathway linking anatomical structure to behavior. Thus distributed corticostriatal processing may mediate the orbitofrontal cortex's influence on behavioral updating, even in the absence of explicit rewards. | 25,143,543 | [
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A new electronic diary tool for mapping and tracking spatial and temporal head pain patterns in migraine. | We present an electronic tool for collecting data on the patterns of migraine headache onset and progression. A digitized map consisting of 44 color-coded segments was defined based on previous reports of migraine pain and the distribution of nerves in the face, head and neck. The map was overlaid on a schematic map of the face, head and neck nerves. Thirty-six patients (N = 36, 28 female/eight male), who met ICDH-II criteria for episodic migraine and had headaches for at least three years, identified all regions where pain typically started and how pain spread and subsequently progressed. Consistent with previous findings, throbbing was the most prevalent quality of migraine pain, always present in 70% of patients surveyed. For the 70% of the patients with throbbing pain, the temple was the onset site of throbbing pain, with no significant difference in the laterality of onset site (58.3% on the right vs. 55.6% on the left hemisphere). The tool was able to capture patterns of pain distribution for throbbing and pressure headache pain and also may be used to assess the change in the pattern of the pain distribution as the disease progresses. The pain map survey may be a useful tool for recording and tracking the temporal pattern of migraine onset both for clinical and research purposes. The tool could be used to create maps of pain locations on a large population scale and thus will be a very useful tool in correlating the temporal nature of headache symptoms with potential mechanisms of disease evolution. | 25,143,550 | [
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A clinical interview versus prospective headache diaries in the diagnosis of menstrual migraine without aura. | The objective of this article is to compare the diagnosis of menstrual migraine without aura (MM) from a clinical interview with prospective headache diaries in a population-based study. A total of 237 women with self-reported migraine in at least half of menstruations were interviewed by a neurologist about headache and diagnosed according to the International Classification of Headache Disorders II (ICHD II). Additionally, the MM criteria were expanded to include other types of migraine related to menstruation. Subsequently, all women were asked to complete three month prospective headache diaries. A total of 123 (52%) women completed both clinical interview and diaries. Thirty-eight women were excluded from the analyses: Two had incomplete diaries and 36 women recorded ≤1 menstruation, leaving 85 diaries eligible for analysis. Sensitivity, specificity, positive and negative predictive value and Kappa for the diagnosis of MM in clinical interview vs. headache diary were 82%, 83%, 90%, 71% and 0.62 (95% CI 0.45-0.79). Using a broader definition of MM, Kappa was 0.64 (95% CI 0.47-0.83). A thorough clinical interview is valid for the diagnosis of MM. When this is undertaken, prospective headache diaries should not be mandatory to diagnose MM but may be necessary to exclude a chance association. | 25,143,553 | [
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Molecular and clinical diagnosis of group A streptococcal pharyngitis in children. | Group A Streptococcus (GAS) pharyngitis is a very common condition causing significant morbidity in children. Accurate diagnosis followed by appropriate antimicrobial therapy is recommended to prevent postinfectious sequelae. Diagnosis of GAS pharyngitis by a rapid antigen detection test (RADT) or culture in the absence of discriminating clinical findings remains challenging. Validation of new sensitive rapid diagnostic tests is therefore a priority. The performance of a loop-mediated isothermal amplification (LAMP) assay (illumigene assay) for the diagnosis of GAS pharyngitis was compared with that of a RADT and standard culture in 361 pediatric throat swab samples. Discrepant results were resolved using an alternate molecular assay. Test results were correlated with clinical presentations in patients positive by either method. The closest estimate of the true prevalence of GAS pharyngitis was 19.7% (71/361 samples). The illumigene assay alone detected 70/71 GAS-positive samples; RADT and culture detected 35/71 and 55/71 samples, respectively. RADT followed by culture confirmation of RADT-negative specimens detected 58/71 cases. The illumigene assay increased identification among children eligible for testing by American College of Physicians (ACP)/American Academy of Family Physicians (AAFP) criteria from 31 to 39 positive cases, five of which were false positives. Analysis of clinical data in GAS-positive patients indicated that a significantly greater proportion of children with McIsaac scores of ≥ 4 tested positive by the illumigene assay versus RADT and culture. Overall, the illumigene assay was much more sensitive and was similarly specific for GAS detection, compared to culture alone, RADT alone, or the ACP/AAFP RADT/culture algorithm. Combining high sensitivity with rapidly available results, the illumigene GAS assay is an appropriate alternative to culture for the laboratory diagnosis of GAS pharyngitis in patients for whom testing is clinically indicated. | 25,143,573 | [
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Dietary calcium, phosphorus, and phytase effects on bird performance, intestinal morphology, mineral digestibility, and bone ash during a natural necrotic enteritis episode. | The objective of this study was to evaluate the effects of dietary Ca, P, and phytase on performance, intestinal morphology, bone ash, and Ca and P digestibility during a necrotic enteritis (NE) outbreak. The 35-d trial was designed as a 2 × 2 × 2 factorial, which included 2 Ca levels (0.6 and 0.9%), 2 P levels (0.3 and 0.45%), and 2 levels of phytase [0 and 1,000 phytase units (FTU)/kg]. Birds were placed on litter from a previous flock that exhibited clinical signs of NE. Birds and feed were weighed on d 12, 19, and 35, and BW gain, feed intake, and feed conversion were calculated. Mortality was recorded daily, and gastrointestinal pH was measured. Tibias and ileal digesta were also collected. Birds began exhibiting clinical signs of NE on d 9, and NE-associated mortality persisted until d 26. Dietary Ca supplemented at 0.9% or inclusion of 1,000 FTU/kg of phytase significantly increased mortality compared with 0.6% Ca or 0 FTU/kg of phytase, respectively. From d 0 to 12, birds fed 0.9% Ca and 0.45% available P with phytase had greater BW gain compared with birds fed 0.6% Ca, 0.45% available P, and phytase. From d 0 to 19, birds fed diets with 0.9% Ca and 0.3% available P had decreased feed intake and improved feed conversion compared with birds fed 0.9% Ca and 0.45% available P. Calcium at 0.9% increased gizzard (d 19) and jejunum (d 12) pH. Phytase supplementation significantly increased Ca digestibility regardless of Ca and P levels of the diets. In addition, diets containing 0.6% Ca and 1,000 FTU/kg of phytase resulted in a significant increase in P digestibility. The results suggest that dietary Ca level may influence NE-associated mortality. In addition, bird performance was affected by interactions of Ca, P, and phytase during the exposure to Clostridium perfringens and the subsequent NE outbreak. Results showed improvements in bird performance when birds were fed 0.6% Ca and 0.3% P in diets supplemented with phytase, which was likely consequent to the influence of Ca in NE pathogenesis. | 25,143,591 | [
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Intersubject variability of and genetic effects on the brain's functional connectivity during infancy. | Infancy is a period featuring a high level of intersubject variability but the brain basis for such variability and the potential genetic/environmental contributions remain largely unexplored. The assessment of the brain's functional connectivity during infancy by the resting state functional magnetic resonance imaging (rsfMRI) technique (Biswal et al., 1995) provides a unique means to probe the brain basis of intersubject variability during infancy. In this study, an unusually large typically developing human infant sample including 58 singletons, 132 dizygotic twins, and 98 monozygotic twins with rsfMRI scans during the first 2 years of life was recruited to delineate the spatial and temporal developmental patterns of both the intersubject variability of and genetic effects on the brain's functional connectivity. Through systematic voxelwise functional connectivity analyses, our results revealed that the intersubject variability at birth features lower variability in primary functional areas but higher values in association areas. Although the relative pattern remains largely consistent, the magnitude of intersubject variability undergoes an interesting U-shaped growth during the first 2 years of life. Overall, the intersubject variability patterns during infancy show both adult-like and infant-specific characteristics (Mueller et al., 2013). On the other hand, age-dependent genetic effects were observed showing significant but bidirectional relationships with intersubject variability. The temporal and spatial patterns of the intersubject variability of and genetic contributions to the brain's functional connectivity documented in this study shed light on the largely uncharted functional development of the brain during infancy. | 25,143,609 | [
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Neonatal amygdala lesions lead to increased activity of brain CRF systems and hypothalamic-pituitary-adrenal axis of juvenile rhesus monkeys. | The current study examined the long-term effects of neonatal amygdala (Neo-A) lesions on brain corticotropin-releasing factor (CRF) systems and hypothalamic-pituitary-adrenal (HPA) axis function of male and female prepubertal rhesus monkeys. At 12-months-old, CSF levels of CRF were measured and HPA axis activity was characterized by examining diurnal cortisol rhythm and response to pharmacological challenges. Compared with controls, Neo-A animals showed higher cortisol secretion throughout the day, and Neo-A females also showed higher CRF levels. Hypersecretion of basal cortisol, in conjunction with blunted pituitary-adrenal responses to CRF challenge, suggest HPA axis hyperactivity caused by increased CRF hypothalamic drive leading to downregulation of pituitary CRF receptors in Neo-A animals. This interpretation is supported by the increased CRF CSF levels, suggesting that Neo-A damage resulted in central CRF systems overactivity. Neo-A animals also exhibited enhanced glucocorticoid negative feedback, as reflected by an exaggerated cortisol suppression following dexamethasone administration, indicating an additional effect on glucocorticoid receptor (GR) function. Together these data demonstrate that early amygdala damage alters the typical development of the primate HPA axis resulting in increased rather than decreased activity, presumably via alterations in central CRF and GR systems in neural structures that control its activity. Thus, in contrast to evidence that the amygdala stimulates both CRF and HPA axis systems in the adult, our data suggest an opposite, inhibitory role of the amygdala on the HPA axis during early development, which fits with emerging literature on "developmental switches" in amygdala function and connectivity with other brain areas. | 25,143,624 | [
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Platelet rich plasma versus laser therapy in lateral epicondylitis of elbow. | Platelet rich plasma (PRP) extract has shown to be a general stimulation for repair and currently used widely in various sports injury. A prospective observational study was done to assess the efficacy of autologous PRP injection in lateral epicondylitis of elbow, and compare the result with low level laser therapy. The trial was conducted at a tertiary care center for a period of 2 years. Eighty-one patients with chronic lateral epicondylitis were divided into two groups. PRP group (n = 39) and laser therapy group (n = 42). The primary analysis included Nirschl pain score, local tenderness, pain on wrist extension, grip strength, elbow swelling were clinically assessed at different interval of followup (minimum followup: 52 weeks) and; clinical and functional outcome evaluated at final followup. The statistical analysis were done. The mean Nirschl pain score decreased significantly from baseline in PRP when compared with low level laser therapy (P ≤ 0.05). Treatment of patients with chronic lateral epicondylitis with PRP extract reduced pain and significantly increased function, exceeding the effect of low level laser therapy on long term followup. Low-level laser therapy is better in the short term period, but on long term followup injection PRP therapy is better than laser therapy in lateral epicondylitis. | 25,143,643 | [
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Stable Estimation of a Covariance Matrix Guided by Nuclear Norm Penalties. | Estimation of a covariance matrix or its inverse plays a central role in many statistical methods. For these methods to work reliably, estimated matrices must not only be invertible but also well-conditioned. The current paper introduces a novel prior to ensure a well-conditioned maximum a posteriori (MAP) covariance estimate. The prior shrinks the sample covariance estimator towards a stable target and leads to a MAP estimator that is consistent and asymptotically efficient. Thus, the MAP estimator gracefully transitions towards the sample covariance matrix as the number of samples grows relative to the number of covariates. The utility of the MAP estimator is demonstrated in two standard applications - discriminant analysis and EM clustering - in this sampling regime. | 25,143,662 | [
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Green nail syndrome treated with the application of tobramycin eye drop. | Green nail syndrome (chromonychia) is a nail disorder characterized by onycholysis and green-black discoloration of the nail bed. This condition is often associated with chronic paronychia. Pseudomonas aeruginosa is the most commonly identified organism in cultures from the affected area. Despite the various treatment options available, removal of the nail is still necessary in many cases. A 35-year-old man presented with dark-greenish discoloration of the nail plate and onycholysis on the left thumbnail. He had been treated with oral antifungal and antibiotic agents for several months; however, the lesion showed no improvement. The diagnosis of green nail syndrome was established after a positive bacterial culture, and on the basis of the antibiotic sensitivity test result, tobramycin eye drop (Tobrex®) was then prescribed. Three weeks later, the nail discoloration almost vanished but the onycholysis remained. Herein, we recommend the application of tobramycin eye drop as an easy and safe treatment option for green nail syndrome. | 25,143,684 | [
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Clinical utility and patient perspectives on the use of extended half-life rFIXFc in the management of hemophilia B. | Hemophilia B is an X-linked genetic disease caused by mutation of the gene for coagulation protein factor IX (FIX), with an incidence of approximately once every 30,000 male births in all populations and ethnic groups. When severe, the disease leads to spontaneous life threatening bleeding episodes. When untreated, most patients die from bleeding complications before 25 years of age. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing FIX. Most patients administer the infusions at home every few days, and must limit their physical activities to avoid abnormal bleeding when the FIX activity levels are below normal. After completing the pivotal Phase III clinical trial, a new therapeutic FIX preparation that has been engineered for an extended half-life in circulation, received regulatory approval in March 2014 in Canada and the US. This new FIX represents a major therapeutic advance for patients with hemophilia B. The half-life is prolonged due to fusion of the native FIX molecule with the normal constant region of immunoglobulin G. This fusion molecule then follows the normal immunoglobulin recirculation pathways through endothelial cells, resulting in prolonged times in circulation. In the clinical trials, over 150 patients successfully used eftrenonacog alfa regularly for more than 1 year to prevent spontaneous bleeding, to successfully treat any bleeding episodes, and to provide effective coagulation for major surgery. All infusions were well tolerated and effective, with no inhibitors detected and no safety concerns. This promising therapy should allow patients to use fewer infusions to maintain appropriate FIX activity levels in all clinical settings. | 25,143,713 | [
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A retrospective analysis focusing on a group of patients with dual diagnosis treated by both mental health and substance use services. | To highlight which demographic, familial, premorbid, clinical, therapeutic, rehabilitative, and assistance factors were related to dual diagnosis, which, in psychiatry, means the co-occurrence of both mental disorder and substance use in the same patient. Our sample (N=145) was chosen from all outpatients with a dual diagnosis treated from January 1, 2012 to July 31, 2012 by both the Mental Health Service and the Substance Use Service of Modena and Castelfranco Emilia, Italy. Patients who dropped out during the study period were excluded. Demographic data and variables related to familial and premorbid history, clinical course, rehabilitative programs, social support and nursing care, and outcome complications were collected. The patients' clinical and functioning conditions during the study period were evaluated. Our patients were mostly men suffering from a cluster B personality disorder. Substance use was significantly more likely to precede psychiatric disease (P<0.001), and 60% of the sample presented a positive familial history for psychiatric or addiction disease or premorbid traumatic factors. The onset age of substance use was related to the period of psychiatric treatment follow-up (P<0.001) and the time spent in rehabilitative facilities (P<0.05), which, in turn, was correlated with personality disorder diagnosis (P<0.05). Complications, which presented in 67% of patients, were related to the high number of psychiatric hospitalizations (P<0.05) and professionals involved in each patient's treatment (P<0.05). Males more frequently presented familial, health, and social complications, whereas females more frequently presented self-threatening behavior (P<0.005). It was concluded that the course of dual diagnosis may be chronic, severe, and disabling, requiring many long-term therapeutic and rehabilitative programs to manage various disabilities. | 25,143,738 | [
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Heart rate variability measured early in patients with evolving acute coronary syndrome and 1-year outcomes of rehospitalization and mortality. | This study sought to examine the prognostic value of heart rate variability (HRV) measurement initiated immediately after emergency department presentation for patients with acute coronary syndrome (ACS). Altered HRV has been associated with adverse outcomes in heart disease, but the value of HRV measured during the earliest phases of ACS related to risk of 1-year rehospitalization and death has not been established. Twenty-four-hour Holter recordings of 279 patients with ACS were initiated within 45 minutes of emergency department arrival; recordings with ≥18 hours of sinus rhythm were selected for HRV analysis (number [N] =193). Time domain, frequency domain, and nonlinear HRV were examined. Survival analysis was performed. During the 1-year follow-up, 94 patients were event-free, 82 were readmitted, and 17 died. HRV was altered in relation to outcomes. Predictors of rehospitalization included increased normalized high frequency power, decreased normalized low frequency power, and decreased low/high frequency ratio. Normalized high frequency >42 ms(2) predicted rehospitalization while controlling for clinical variables (hazard ratio [HR] =2.3; 95% confidence interval [CI] =1.4-3.8, P=0.001). Variables significantly associated with death included natural logs of total power and ultra low frequency power. A model with ultra low frequency power <8 ms(2) (HR =3.8; 95% CI =1.5-10.1; P=0.007) and troponin >0.3 ng/mL (HR =4.0; 95% CI =1.3-12.1; P=0.016) revealed that each contributed independently in predicting mortality. Nonlinear HRV variables were significant predictors of both outcomes. HRV measured close to the ACS onset may assist in risk stratification. HRV cut-points may provide additional, incremental prognostic information to established assessment guidelines, and may be worthy of additional study. | 25,143,740 | [
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Initial LDH level can predict the survival benefit from bevacizumab in the first-line setting in Chinese patients with metastatic colorectal cancer. | Markers to predict the efficacy of bevacizumab treatment have been not fully validated in most cancers, including metastatic colorectal cancer (mCRC). The aim of this study was to investigate the potential role of lactate dehydrogenase (LDH) in predicting the survival benefit from first-line bevacizumab treatment, in Chinese patients with mCRC. All the patients were diagnosed with mCRC at the Sun Yat-sen University Cancer Center from 2003 to 2013. The study group and the control group were classified by receiving bevacizumab or not. The serum LDH value of all the patients had been detected before the first-line treatment. The primary end point was progression-free survival (PFS). The median PFS of the study and the control group (patients who received bevacizumab or not) was 11.3 and 9.1 months, respectively (P=0.004). In the control group, the median PFS of the high LDH level and the low LDH level groups was 6.9 and 10.2 months, respectively (P<0.001). However, in the study group, the corresponding median PFS was 9.9 and 11.9 months, respectively (P=0.145). In addition, for the low LDH level group, the median PFS was 11.9 and 10.2 months for patients who received bevacizumab or not, respectively (P=0.066); however, the median PFS of patients receiving bevacizumab or not was significantly different in the high LDH level group (9.9 and 6.9 months, respectively) (P=0.012). The addition of bevacizumab in the first-line treatment setting could improve the PFS of mCRC patients notably. However, the benefit could only be potentially reflected on patients with high serum LDH level. | 25,143,746 | [
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Dietary pattern and asthma: a systematic review and meta-analysis. | The literature on the relationship between diet and asthma has largely focused on individual nutrients, with conflicting results. People consume a combination of foods from various groups that form a dietary pattern. Studying the role of dietary patterns in asthma is an emerging area of research. The purpose of this study was to systematically review dietary patterns and asthma outcomes in adults and children, to review maternal diet and child asthma, and to conduct a meta-analysis on the association between asthma prevalence and dietary patterns in adults. We searched Medline, Scopus, and ISI Web of Knowledge up to January 2014. Two researchers independently reviewed studies meeting the inclusion criteria using the American Dietetic Association quality criteria. A linear mixed model was used to derive the pooled effect size (95% confidence interval) for each of three dietary pattern categories (healthy, unhealthy, and neutral). Thirty-one studies were identified (16 cross-sectional, one case-control, 13 cohort, and one randomized controlled trial), including 12 in adults, 13 in children, five in pregnant woman-child pairs, and one in both children and pregnant woman-child pairs. Six of the 12 adult studies reported significant associations between dietary patterns and asthma outcomes (eg, ever asthma and forced expiratory volume in one second). Seven of ten studies examining the Mediterranean diet showed protective effects on child asthma and/or wheeze. Four of the six studies in mother-child pairs showed that maternal dietary patterns during pregnancy were not associated with child asthma or wheeze. The meta-analysis including six adult studies, the primary outcome of which was the prevalence of current or ever asthma, showed no association with healthy, unhealthy, or neutral dietary patterns. The evidence suggests no association of dietary patterns with asthma prevalence in adults or of maternal diet with child asthma or wheeze. The Mediterranean diet in children may prevent asthma or wheeze, but randomized controlled trials are lacking. | 25,143,747 | [
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A randomized, double-blind, placebo-controlled clinical trial evaluating Dermytol(®) cream for the treatment of actinic keratoses. | Actinic keratosis lesions (AKs) have the potential to develop into squamous cell carcinoma (SCC) and thus therapies to prevent SCC development from AKs are warranted. The aim of this study was to assess the effects of a 3 month application of a canola phenolic acid-based cream (CPA) on AK lesions. This was a randomized, double-blind, placebo-controlled, 12 week clinical study conducted at a single-center in Santo Domingo, Dominican Republic. Forty-five subjects (30 CPA and 15 placebo), aged 45-85 years with 3-10 AKs within a 20 cm(2) treatment area (scalp, forehead, dorsal forearm, neck, or back of hand) were enrolled. The primary outcome was complete or partial lesion clearance and the secondary outcome was safety of CPA. Although complete AK lesion clearance was not seen in this study, a significant reduction in the mean change from baseline in the average lesion area was observed at weeks 3 (P=0.002), 6 (P<0.001), and 12 (P<0.001) in the CPA group, but only at weeks 6 and 12 in the placebo group (P=0.005 and P=0.002, respectively). Furthermore, the proportion of participants with a $10% decrease in average lesion area was significantly higher in the CPA group than the placebo group at weeks 3 (P=0.05) and 6 (P=0.02), and showed a trend at week 12 (P=0.06). A subset analysis of the change in average lesion area based upon the total lesion area at baseline revealed that CPA elicited a greater reduction than placebo (2×) in participants with a baseline total AK lesion area of 100-500 mm(2) than in participants with a total area <100 mm(2) (1.3×). The results of this study and previous in vitro studies suggest a potential role for CPA in the treatment of AK lesions and the prevention of SCC development. | 25,143,750 | [
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Role of uterine forces in intrauterine device embedment, perforation, and expulsion. | The purpose of this study was to examine factors that could help reduce primary perforation during insertion of a framed intrauterine device (IUD) and to determine factors that contribute in generating enough uterine muscle force to cause embedment and secondary perforation of an IUD. The objective was also to evaluate the main underlying mechanism of IUD expulsion. We compared known IUD insertion forces for "framed" devices with known perforation forces in vitro (hysterectomy specimens) and known IUD removal forces and calculated a range of possible intrauterine forces using pressure and surface area. These were compared with known perforation forces. IUD insertion forces range from 1.5 N to 6.5 N. Removal forces range from 1 N to 5.8 N and fracture forces from 8.7 N to 30 N depending upon device. Measured perforation forces are from 20 N to 54 N, and calculations show the uterus is capable of generating up to 50 N of myometrial force depending on internal pressure and surface area. Primary perforation with conventional framed IUDs may occur if the insertion pressure exceeds the perforation resistance of the uterine fundus. This is more likely to occur if the front end of the inserter/IUD is narrow, the passage through the cervix is difficult, and the procedure is complex. IUD embedment and secondary perforation and IUD expulsion may be due to imbalance between the size of the IUD and that of the uterine cavity, causing production of asymmetrical uterine forces. The uterine muscle seems capable of generating enough force to cause an IUD to perforate the myometrium provided it is applied asymmetrically. A physical theory for IUD expulsion and secondary IUD perforation is given. | 25,143,756 | [
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A mixed methods study of student perceptions of using standardized patients for learning and evaluation. | Educators recognize the value of using standardized patients (SPs) when teaching and evaluating clinical skills in rehabilitation entry-to-practice education programs but have published little supporting evidence and have yet to evaluate programmatic SP use from a student perspective. This study explored occupational and physical therapy students' perceptions of SP use in their professional education. Recruiting current and graduated students, we conducted a two-phase mixed-methods sequential-explanatory study integrating data from a quantitative survey (phase 1) and qualitative focus groups with representative students (phase 2). Quantitative data were used to direct the second phase and informed selection of a purposive sample to participate in four focus groups (N=12). The 24-item online survey obtained a 32% response rate (N=167). Mean ratings were high, but significant differences were found between the four subsections of Teaching, SP Experience, Feedback, and Evaluation (P=0.000). Secondary analyses revealed significant differences based on sex, program, and age. Qualitative analysis revealed that students found SP use especially helpful earlier in their program to bridge classroom teaching and clinical practice. Students in the occupational and physical therapy programs approached SP interactions differently in terms of the authenticity, personal investment, and value of SP feedback. Educator feedback was perceived as reflective of technical skill, and SP feedback reflective of therapeutic value, which students prioritized differently. Students identified a preferential continuum of options for learning and practicing skills, ranging from peers and instructors through SPs to actual patients. SPs were perceived as most useful early on in the professional education program, serving to bolster self-confidence and prepare students for clinical fieldwork. Discipline-specific differences impact the perception of SP use and value. Educators need to be aware of pragmatic and contextual issues when using SPs for examination purposes, including repeated exposure to the same actor. | 25,143,758 | [
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Prophylactic Appendectomy during Laparoscopic Surgery for Other Conditions. | Acute appendicitis remains the most common surgical emergency. Laparoscopy has gained increasing favor as a method of both investigating right iliac fossa pain and treating the finding of appendicitis. A question arises: what to do with an apparent healthy appendix discovered during laparoscopic surgery for other pathology. We present a case of unilateral hydroureteronephrosis complicated with rupture of the renal pelvis, due to gangrenous appendicitis with abscess of the right iliopsoas muscle and periappendicular inflammation in a 67-year-old woman, who underwent laparoscopic right annessiectomy for right ovarian cyst few years earlier, in which a healthy appendix was left inside. There is a lack of consensus in the literature about what to do with a normal appendix. The main argument for removing an apparently normal appendix is that endoluminal appendicitis may not be recognized during surgery, leading to concern that an abnormal appendix is left in place. Because of a lack of evidence from randomized trials, it remains unclear whether the benefits of routine elective coincidental appendectomy outweigh the costs and risks of morbidity associated with this prophylactic procedure. Nevertheless, it appears, from limited data, that women aged 35 years and under benefit most from elective coincidental appendectomy. | 25,143,764 | [
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Melatonin's Effect in Febrile Seizures and Epilepsy. | Recognition of risk factors for febrile seizures (FS) and epilepsy is essential. Studies regarding the role of melatonin in these convulsive disorders are limited. This study determines the relationship between serum melatonin levels and FS and epilepsy in children. A population of 111 children with simple FS, complex FS, and epilepsy (37 children per group, respectively) were included as case groups. In addition, 37 febrile children without seizures comprised the control group. Serum melatonin levels were measured and compared between all groups. The serum melatonin levels in the simple, complex FSs, and epilepsy groups were 2, 2.4, and 2 pg/ml, respectively. The serum melatonin level in the control group was 2.1pg/ml. Moreover, there were no significant differences observed while comparing the case groups. The present study reveals that there is no association between serum melatonin level and simple or complex FS and epilepsy. It appears that melatonin plays no significant role in these convulsive disorders. | 25,143,770 | [
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Is "benign Childhood Epilepsy with Centrotemporal Spikes" Always Benign? | To determine the prevalence of associated behavioral problems and prognosis with Benign Childhood Epilepsy with CentroTemporal Spikes (BCECTS). Descriptive, Cross Sectional study that was conducted from October 2009 to April 2013 in the Department of Pediatric Neurology, the Children's Hospital Taif, KSA. This study was conducted after approval from the Ethics Committee of the Children's Hospital Taif, Saudi Arabia. Thirty-two patients from the age of 3 to 10 years old were recruited from the pediatric neurology clinic over a period of 4 years. All the patients were selected based on history, EEGs, and neuropsychological and neurological examinations. EEGs were performed for all the patients while in awake and sleep states. Those who had centrotemporal discharges were included in the study. All the patients also underwent a brain MRI. Only two patients had mild cortical atrophy but developmentally they were normal. In our study, prevalence of BRE is 32/430 (7.44%). Among the 32 cases, 24 were male and eight were female. Six cases out of 32 indicated a family history of BRE. Twenty-eight cases had unilateral right sided centrotemporal discharges and four had bilateral discharges. It is possible that for BECTS, a high number of seizures might play an important role in the development of mild cognitive impairment and/or behavior disturbances. | 25,143,772 | [
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Paroxysmal nocturnal hemoglobinuria presenting as cerebral venous sinus thrombosis: a case report. | Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare type of acquired hemolytic anemia that is frequently associated with thrombophilia. It may rarely present with cerebral venous sinus thrombosis, which manifests clinically with signs of raised intracranial pressure and requires lifelong anticoagulation therapy. One such rare presentation was seen in a 28 years old male who had history of recurrent episodes of passing red colored urine and this time presented with severe headache. He was diagnosed to have cerebral venous sinus thrombosis and on further workup was found to be suffering from PNH. | 25,143,784 | [
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Pachymic Acid Enhances Pentobarbital-Induced Sleeping Behaviors via GABAA-ergic Systems in Mice. | This study was investigated to know whether pachymic acid (PA), one of the predominant triterpenoids in Poria cocos (Hoelen) has the sedative-hypnotic effects, and underlying mechanisms are mediated via γ-aminobutyric acid (GABA)-ergic systems. Oral administration of PA markedly suppressed locomotion activity in mice. This compound also prolonged sleeping time, and reduced sleep latency showing synergic effects with muscimol (0.2 mg/kg) in shortening sleep onset and enhancing sleep time induced by pentobarbital, both at the hypnotic (40 mg/kg) and sub-hypnotic (28 mg/kg) doses. Additionally, PA elevated intracellular chloride levels in hypothalamic primary cultured neuronal cells of rats. Moreover, Western blotting quantitative results showed that PA increased the amount of protein level expression of GAD65/67 over a broader range of doses. PA increased α- and β-subunits protein levels, but decreased γ-subunit protein levels in GABAA receptors. The present experiment provides evidence for the hypnotic effects as PA enhanced pentobarbital-induced sleeping behaviors via GABAA-ergic mechanisms in rodents. Taken together, it is proposed that PA may be useful for the treatment of sleep disturbed subjects with insomnia. | 25,143,810 | [
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Routes and mechanisms of extracellular vesicle uptake. | Extracellular vesicles (EVs) are small vesicles released by donor cells that can be taken up by recipient cells. Despite their discovery decades ago, it has only recently become apparent that EVs play an important role in cell-to-cell communication. EVs can carry a range of nucleic acids and proteins which can have a significant impact on the phenotype of the recipient. For this phenotypic effect to occur, EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. EVs are of therapeutic interest because they are deregulated in diseases such as cancer and they could be harnessed to deliver drugs to target cells. It is therefore important to understand the molecular mechanisms by which EVs are taken up into cells. This comprehensive review summarizes current knowledge of EV uptake mechanisms. Cells appear to take up EVs by a variety of endocytic pathways, including clathrin-dependent endocytosis, and clathrin-independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization. Indeed, it seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route. The uptake mechanism used by a given EV may depend on proteins and glycoproteins found on the surface of both the vesicle and the target cell. Further research is needed to understand the precise rules that underpin EV entry into cells. | 25,143,819 | [
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The nasal cavity microbiota of healthy adults. | The microbiota of the nares has been widely studied. However, relatively few studies have investigated the microbiota of the nasal cavity posterior to the nares. This distinct environment has the potential to contain a distinct microbiota and play an important role in health. We obtained 35,142 high-quality bacterial 16S rRNA-encoding gene sequence reads from the nasal cavity and oral cavity (the dorsum of the tongue and the buccal mucosa) of 12 healthy adult humans and deposited these data in the Sequence Read Archive (SRA) of the National Center for Biotechnology Information (NCBI) (Bioproject: PRJNA248297). In our initial analysis, we compared the bacterial communities of the nasal cavity and the oral cavity from ten of these subjects. The nasal cavity bacterial communities were dominated by Actinobacteria, Firmicutes, and Proteobacteria and were statistically distinct from those on the tongue and buccal mucosa. For example, the same Staphylococcaceae operational taxonomic unit (OTU) was present in all of the nasal cavity samples, comprising up to 55% of the community, but Staphylococcaceae was comparatively uncommon in the oral cavity. There are clear differences between nasal cavity microbiota and oral cavity microbiota in healthy adults. This study expands our knowledge of the nasal cavity microbiota and the relationship between the microbiota of the nasal and oral cavities. | 25,143,824 | [
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Case report: a 37-year-old male with telangiectasias, polycythemia vera, perinephric fluid collections, and intrapulmonary shunting. | The TEMPI syndrome was recently described in 2011, and is characterized by the constellation of five hallmarks: Telangiectasias, Erythrocytosis and elevated Erythropoietin, Monoclonal gammopathy, Perinephric fluids collections, and Intrapulmonary shunting. The underlying pathophysiology is unknown, though it has been postulated that the monoclonal gammopathy may play a causal role. A 37-year-old non-smoking male presented to our institution with a fever and the sensation of fullness in the right flank. His exam was notable for telangiectasias, clubbing of the fingernails, plethora, and a palpable bulge in the right flank. Renal ultrasound demonstrated bilateral perinephric fluid collections. Laboratory evaluation revealed erythrocytosis with low serum erythropoietin, and testing for the JAK2V617F mutation was positive, confirming a diagnosis of polycythemia vera. Though his room air saturation was normal at rest, it decreased dramatically with exercise, felt to be secondary to microscopic intrapulmonary shunting. The patient's presentation is very similar to that of the TEMPI syndrome, a very rare syndrome of which there have been six published cases. In contrast to the TEMPI syndrome where the erythrocytosis is driven by highly elevated serum erythropoietin, our patient was found to have polycythemia vera. Also in contrast to the other patients with TEMPI syndrome, our patient did not have an identifiable monoclonal gammopathy. Our patient responded to treatment with hydroxyurea. His erythrocytosis, perinephric fluid collections, and telangiectasias resolved over the course of six months. The intrapulmonary shunting has continued to gradually improve with treatment, suggesting that this is an entirely reversible process. Our case is the first to describe the combination of polycythemia vera, telangiectasias, perinephric fluid collections, and intrapulmonary shunting. The presentation is highly similar to the previously described TEMPI syndrome, though calls into question the potential importance of the monoclonal gammopathy. Our patient demonstrated a response to treatment with hydroxyurea, while patients with the TEMPI syndrome have shown responses to plasma-cell directed therapies such as bortezomib. | 25,143,825 | [
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Evaluation of pachymetric measurements with scheimpflug photography-based system and optical coherence tomography pachymetry at different stages of keratoconus. | The aim of this study was to compare the central and peripheral pachymetric measurements determined with Sirius system and Visante OCT and evaluate the agreement between them at different stages of keratoconus. Measurements were not significantly different in all patients and subgroups and showed high correlation for the corneal thicknesses of the entire cornea in different stages of keratoconus. | 25,143,828 | [
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Minimally invasive esophagectomy for esophageal cancer: the first experience from Pakistan. | Two common procedures for esophageal resection are Ivor Lewis esophagectomy and transhiatal esophagectomy. Both procedures have high morbidity rates of 20-46%. Minimally invasive esophagectomy has been introduced to decrease morbidity. We report initial experience of MIE to determine the morbidity and mortality associated with this procedure during learning phase. Patients undergoing MIE at our institute from January 2011 to May 2013 were reviewed. Record was kept for any morbidity and mortality. Descriptive statistics were presented as frequencies and continuous variables were presented as median. Survival analysis was performed using Kaplan Meier curves. We performed 51 minimally invasive esophagectomies. Perioperative morbidity was in 16 (31.37%) patients. There were 3 (5.88%) anastomotic leaks. We encountered 1 respiratory complication. Reexploration was required in 3 (5.88%) patients. Median operative time was 375 minutes. Median hospital stay was 10 days. The most frequent long-term morbidity was anastomotic narrowing observed in 5 (9.88%) patients. There were no perioperative mortalities. Our mean overall survival was 37.66 months (95% confidence interval 33.75 to 41.56 months). Mean disease-free survival was 24.43 months (95% CI 21.26 to 27.60 months). Minimally invasive esophagectomy, when performed in the learning phase, has acceptable morbidity and mortality. | 25,143,832 | [
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Aggressive Subcutaneous Panniculitis-Like CD30+ Peripheral T-Cell Lymphoma with Diffuse EBER Expression. | T-cell lineage lymphoma with an intense membranous and paranuclear CD30 expression in the absence of ALK1 raises a differential diagnosis of peripheral T-cell lymphoma (PTCL), NOS and anaplastic large cell lymphoma (ALCL), ALK negative. However, Epstein-Barr virus is consistently negative in ALCL and is not considered an implicating factor in its pathogenesis. We describe a case of T-cell lymphoma showing anaplastic large cell morphology with scattered hallmark cells and a uniform CD30 and Epstein-Barr virus encoded early RNA (EBER) expression that primarily involved the subcutaneous tissue at presentation. On incisional biopsy, the neoplastic cells were positive for CD3, CD2, and CD30 while negative for LCA, CD20, PAX5, CD56, ALK1, and cytotoxic granules. Molecular analysis identified a positive T-cell receptor (beta and gamma) gene rearrangement by PCR. Proliferation index approached 100% and the patient had a rapidly progressive course; the subcutaneous lesions more than doubled in size within couple of weeks with new evidence for widespread systemic involvement. This case emphasizes a rare EBV association with a CD30 positive T-cell lymphoma where the morphologic and immunophenotypic findings are otherwise nondiscriminatory between PTCL, NOS and ALCL, ALK negative. | 25,143,841 | [
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Isolated asymptomatic short sternum in a healthy young girl. | Congenital sternal defects are rare deformities frequently associated with other anomalies of the chest wall and other organ systems. Although pectus excavatum, pectus carinatum, and cleft sternum can present as isolated deformity, in most cases they are associated with heart and inner organs anomalies and described as symptoms of syndromes like Marfan syndrome, Noonan syndrome, Poland anomaly, and Cantrell pentalogy. In contrast, the etiology of an isolated defect is not well understood. We observed a short sternum (dysmorphic manubrium, hypoplastic body, and complete absence of the xiphoid process) in a completely asymptomatic 13-year-old woman. A comprehensive instrumental exams panel was performed to exclude associated anomalies of the heart and of the other organ systems. The patient was completely asymptomatic and she did not need any medical or surgical treatment. To our knowledge, this is the first case of isolated short sternum reported in literature. | 25,143,854 | [
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Initial in vivo PET imaging of 5-HT1A receptors with 3-[(18)F]mefway. | 4-trans-[(18)F]Mefway is a PET radiotracer with high affinity for 5-HT1A receptors. Our preliminary work indicated the positional isomer, 3-[(18)F]mefway, would be suitable for PET imaging of 5-HT1A receptors. We now compare the in vivo behaviour of 3-mefway with 4-mefway to evaluate 3-[(18)F]mefway as a potential 5-HT1A PET radiotracer. Two male rhesus macaques were given bolus injections of both 3- and 4-trans-[(18)F]mefway in separate experiments. 90 minute dynamic PET scans were acquired. TACs were extracted in the mesial temporal lobe (MTL) and caudal anterior cingulate gyrus (cACg). The cerebellum (CB) was used as a reference region. In vivo behavior of the radiotracers in the CB was compared based upon the ratio of normalized PET uptake for 3- and 4-trans-[(18)F]mefway. Specific binding was compared by examining MTL/CB and cACg/CB ratios. The subject-averaged ratio of 3-[(18)F]mefway to 4-trans-[(18)F]mefway in the cerebellum was 0.96 for 60-90 minutes. MTL/CB reached plateaus of ~2.7 and ~6 by 40 minutes and 90 minutes for 3- and 4-trans-[(18)F]mefway, respectively. cACg/CB reached plateaus of ~2.5 and ~6 by 40 minutes and 70 minutes for 3- and 4-trans-[(18)F]mefway, respectively. The short pseudoequilibration times and sufficient uptake of 3-[(18)F]mefway may be useful in studies requiring short scan times. Furthermore, the similar nondisplaceable clearance in the CB to 4-trans-[(18)F]mefway suggests the lower BPND of 3-[(18)F]mefway is due to a lower affinity. The lower affinity of 3-[(18)F]mefway may make it useful for measuring changes in endogenous 5-HT levels, however, this remains to be ascertained. | 25,143,866 | [
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Molecular analysis of interleukin-25 exons 1 and 2 and its serum levels in Iranian patients with multiple sclerosis. | Overexpression of Interleukin-17 (IL-17) family has been shown in a variety of autoimmune diseases. IL-25 (IL-17E), as a member of this family of cytokines, induces the overexpression of IL-13 and impedes Th17/IL-17 responses. In the present study potential single nucleotide polymorphisms (SNP) of IL-25, its serum level in Multiple Sclerosis (MS) patients have been surveyed. Blood samples were obtained from 100 Relapsing-Remitting MS cases, and 100 healthy controls. Serum levels of IL-25 were measured by ELISA. IL-25 exons 1 and 2 were sequenced. IL-25 serum levels investigation showed significant association in cases compared to controls. Molecular analysis of IL-25exons 1 and 2 depicted significant differences in polymorphisms of exon 2 between two groups of study. However, no significant differences were found in polymorphisms for IL-25 exon. These results demonstrate that serum levels of IL-25 are reduced in MS patients compared to controls. This is the first study in Iran that shows polymorphisms in IL-25 among MS patients. Considering the role of IL-25 in suppression of the effects of IL-17A and active phase of Experimental Autoimmune Encephalomyelitis (EAE) in vivo, this cytokine seems to have therapeutic potentials for autoimmune diseases like MS. | 25,143,869 | [
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Modified case based learning: Our experience with a new module for pharmacology undergraduate teaching. | The undergraduate teaching in pharmacology has always been a challenging task for medical teachers. Traditional lecture format is monotonous and a passive way of learning. There is a need to shift the educational focus from content centered to case based. In an effort to create interest and further improve the student learning, we have introduced simulated bedside teaching sessions as case based learning (CBL) module (modified CBL-[mCBL]) for 2(nd) professional MBBS students. A case scenario of a clinical disease condition was prepared in consultation with a clinician. During the session, the case was presented along with discussion on the disease process, its management and rational drug use. Students were encouraged to participate actively. After the session, students were requested to fill the feedback questionnaire anonymously (both open-ended questions and responses on Likert scale). According to the students, factors such as clinical orientation, interactivity and re-enforcement of important points helped them to learn better. Majority of the students (76.09%) found the sessions to be better than theory lectures and tutorials. The fact that the interactive component of departmental feedback (taken at the institutional level) has improved during the last 2 years could be attributed to the introduction of these sessions. mCBL (in the presence of departmental faculty and concerned clinician) is a good method of integrating pharmacology with clinical subjects. To make such sessions more reliable, the next planned step is to assess the knowledge gained by the students during such sessions in the future. | 25,143,883 | [
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Diabetes mellitus and suicide. | Relationship of diabetes mellitus (DM) with metal health disorders such as depression has been explored extensively in the published literatures. However, association of diabetes mellitus with suicidal tendencies has been evaluated less extensively. The present narrative review aimed to assess the literature relating to diabetes mellitus and suicide. As a part of the review, Pubmed and Google Scholar databases were searched for English language peer reviewed published studies with keywords relating to diabetes and suicide. Additional references were identified using cross-references. The available literature suggests that suicidal ideas and attempts are more frequent in patients with diabetes mellitus than healthy or medically ill controls. Although, a few studies report evidence to the contrary. Suicide accounts for a large proportion of deaths in patients with diabetes mellitus type I (T1DM), and their mortality rate is higher than that of age matched control population. Psychological morbidity, including depression, precedes suicidal ideas and attempts; though many other factors can be hypothesized to impact and modulate this association. A common method of suicide attempt in patients with diabetes includes uses of high doses of insulin and its congeners or medications to treat the disease. Regular screening and prompt treatment of depression and suicidality is suggested for patients with DM. | 25,143,900 | [
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RET mutations in a large indian family with medullary thyroid carcinoma. | Medullary thyroid carcinoma (MTC) is a tumor arising from the para follicular (C) cells of the thyroid gland and can occur either sporadically or as part of an inherited syndrome. A proportion of these cases carry an autosomal dominant mutation in the RET (REarranged during Transfection) proto-oncogene. Screening for these mutations in the affected patients and the carriers "at risk" which includes the first-degree relatives is of utmost importance for early detection and prompt treatment including prophylactic thyroidectomy in cases that harbor these mutations. This report presents details of screening and subsequent follow-up of a large Indian family, where the index case was found to carry p. Cys634Ser mutation involving exon 11 of the RET gene. These data are of value considering the paucity of information within the region in context of screening large families affected by these mutations. | 25,143,909 | [
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Does pulsed magnetic field therapy influence nerve regeneration in the median nerve model of the rat? | The aim of this study was to evaluate the impact of pulsed magnetic field therapy on peripheral nerve regeneration after median nerve injury and primary coaptation in the rat. Both median nerves were surgically exposed and denervated in 24 female Wistar rats. A microsurgical coaptation was performed on the right side, whereas on the left side a spontaneous healing was prevented. The study group underwent a daily pulsed magnetic field therapy; the other group served as a control group. The grasping force was recorded 2 weeks after the surgical intervention for a period of 12 weeks. The right median nerve was excised and histologically examined. The histomorphometric data and the functional assessments were analyzed by t-test statistics and one-way ANOVA. One-way ANOVA indicated a statistically significant influence of group affiliation and grasping force (P = 0.0078). Grasping strength was higher on a significant level in the experimental group compared to the control group permanently from the 9th week to the end of the study. T-test statistics revealed a significantly higher weight of the flexor digitorum sublimis muscle (P = 0.0385) in the experimental group. The histological evaluation did not reveal any statistically significant differences concerning the histomorphometric parameters. Our results suggest that the pulsed magnetic field therapy has a positive influence on the functional aspects of neural regeneration. More studies are needed to precisely evaluate and optimize the intensity and duration of the application. | 25,143,937 | [
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Test anxiety levels of board exam going students in Tamil Nadu, India. | The latest report by the National Crime Records Bureau has positioned Tamil Nadu as the Indian state with highest suicide rate. At least in part, this is happening due to exam pressure among adolescents, emphasizing the imperative need to understand the pattern of anxiety and various factors contributing to it among students. The present study was conducted to analyze the level of state anxiety among board exam attending school students in Tamil Nadu, India. A group of 100 students containing 50 boys and 50 girls from 10th and 12th grades participated in the study and their state anxiety before board exams was measured by Westside Test Anxiety Scale. We found that all board exam going students had increased level of anxiety, which was particularly higher among boys and 12th standard board exam going students. Analysis of various demographic variables showed that students from nuclear families presented higher anxiety levels compared to their desired competitive group. Overall, our results showing the prevalence of state anxiety among board exam going students in Tamil Nadu, India, support the recent attempt taken by Tamil Nadu government to improve student's academic performance in a healthier manner by appointing psychologists in all government schools. | 25,143,938 | [
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The role of oxidative stress and inflammation in cardiovascular aging. | Age is an independent risk factor of cardiovascular disease, even in the absence of other traditional factors. Emerging evidence in experimental animal and human models has emphasized a central role for two main mechanisms of age-related cardiovascular disease: oxidative stress and inflammation. Excess reactive oxygen species (ROS) and superoxide generated by oxidative stress and low-grade inflammation accompanying aging recapitulate age-related cardiovascular dysfunction, that is, left ventricular hypertrophy, fibrosis, and diastolic dysfunction in the heart as well as endothelial dysfunction, reduced vascular elasticity, and increased vascular stiffness. We describe the signaling involved in these two main mechanisms that include the factors NF-κB, JunD, p66(Shc), and Nrf2. Potential therapeutic strategies to improve the cardiovascular function with aging are discussed, with a focus on calorie restriction, SIRT1, and resveratrol. | 25,143,940 | [
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Identifying hierarchical and overlapping protein complexes based on essential protein-protein interactions and "seed-expanding" method. | Many evidences have demonstrated that protein complexes are overlapping and hierarchically organized in PPI networks. Meanwhile, the large size of PPI network wants complex detection methods have low time complexity. Up to now, few methods can identify overlapping and hierarchical protein complexes in a PPI network quickly. In this paper, a novel method, called MCSE, is proposed based on λ-module and "seed-expanding." First, it chooses seeds as essential PPIs or edges with high edge clustering values. Then, it identifies protein complexes by expanding each seed to a λ-module. MCSE is suitable for large PPI networks because of its low time complexity. MCSE can identify overlapping protein complexes naturally because a protein can be visited by different seeds. MCSE uses the parameter λ_th to control the range of seed expanding and can detect a hierarchical organization of protein complexes by tuning the value of λ_th. Experimental results of S. cerevisiae show that this hierarchical organization is similar to that of known complexes in MIPS database. The experimental results also show that MCSE outperforms other previous competing algorithms, such as CPM, CMC, Core-Attachment, Dpclus, HC-PIN, MCL, and NFC, in terms of the functional enrichment and matching with known protein complexes. | 25,143,945 | [
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The genetic structure of wild Orobanche cumana Wallr. (Orobanchaceae) populations in eastern Bulgaria reflects introgressions from weedy populations. | Orobanche cumana is a holoparasitic plant naturally distributed from central Asia to south-eastern Europe, where it parasitizes wild Asteraceae species. It is also an important parasitic weed of sunflower crops. The objective of this research was to investigate genetic diversity, population structure, and virulence on sunflower of O. cumana populations parasitizing wild plants in eastern Bulgaria. Fresh tissue of eight O. cumana populations and mature seeds of four of them were collected in situ on wild hosts. Genetic diversity and population structure were studied with SSR markers and compared to weedy populations. Two main gene pools were identified in Bulgarian populations, with most of the populations having intermediate characteristics. Cross-inoculation experiments revealed that O. cumana populations collected on wild species possessed similar ability to parasitize sunflower to those collected on sunflower. The results were explained on the basis of an effective genetic exchange between populations parasitizing sunflower crops and those parasitizing wild species. The occurrence of bidirectional gene flow may have an impact on wild populations, as new physiological races continuously emerge in weedy populations. Also, genetic variability of wild populations may favour the ability of weedy populations to overcome sunflower resistance mechanisms. | 25,143,963 | [
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RSSI-based smooth localization for indoor environment. | Radio frequency (RF) technique, for its better penetrability over traditional techniques such as infrared or ultrasound, is widely used for indoor localization and tracking. In this paper, three novel measurements, point decision accuracy, path matching error and wrong jumping ratio, are firstly defined to express the localization efficiency. Then, a novel RSSI-based smooth localization (RSL) algorithm is designed, implemented, and evaluated on the WiFi networks. The tree-based mechanism determines the current position and track of the entity by assigning the weights and accumulative weights for all collected RSSI information of reference points so as to make the localization smooth. The evaluation results indicate that the proposed algorithm brings better localization smoothness of reducing 10% path matching error and 30% wrong jumping ratio over the RADAR system. | 25,143,988 | [
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Gorgonian disease outbreak in the Gulf of Naples: pathology reveals cyanobacterial infection linked to elevated sea temperatures. | In recent years, mass mortality events of benthic invertebrates in the Mediterranean Sea have been documented to coincide with the increased seawater temperatures associated with global climate change. Following a disease outbreak in gorgonians during the summer seasons of 2008 and 2009 in the Gulf of Naples (Tyrrhenian Sea), we conducted gross and microscopic analyses of healthy and diseased specimens of Eunicella cavolinii and E. singularis using both light and electron microscopy (SEM). Macroscopically, diseased colonies exhibited evident tissue thinning, and dead colonies showed a complete loss of polyps and coenenchyme, exposing their skeletons to settlement by fouling organisms. Histopathology revealed chronic inflammatory lesions at the polyp and axial level, characterized by amoebocyte infiltration of tissue accompanied by new apposition of melanin/gorgonin sheets. We interpreted this response as a defense against different kinds of pathogens-identified as mainly a heterogeneous consortium of filamentous cyanobacteria-and which gradually led to enlargement and hardening of the coral axis, which resembled a wood-like structure at the final stage of the disease. These processes elicited the formation of multiple inflammatory nodules and capsules, some of which were macroscopically visible. A parallel 16S rRNA and ITS analysis of the diseased tissue identified Synechococcus, Arthrospira and other uncultured cyanobacteria grouped within the Oscillatoriales. These results suggest that a cyanobacterial consortium is involved in the pathogenesis of the inflammatory disease leading to the mortality of Gorgoniaceae in the area. Finally, there were anomalously high temperatures (up to 25°C) between 10 and 20 m depth during the sampling period, particularly in June 2009. This supports the hypothesis that the coral skeleton may serve as a reservoir for the pathogens in cooler seasons, with warmer conditions leading to pathogen reactivation and recurring mortality events. | 25,144,119 | [
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Total fructose intake and risk of hypertension: a systematic review and meta-analysis of prospective cohorts. | Although most controlled feeding trials have failed to show an adverse effect of fructose on blood pressure, concerns continue to be raised regarding the role of fructose in hypertension. To quantify the association between fructose-containing sugar (high-fructose corn syrup, sucrose, and fructose) intake and incident hypertension, a systematic review and meta-analysis of prospective cohort studies was undertaken. MEDLINE, EMBASE, CINAHL and the Cochrane Library (through February 5, 2014) were searched for relevant studies. Two independent reviewers reviewed and extracted relevant data. Risk estimates were aggregated comparing the lowest (reference) quintile with highest quintile of intake using inverse variance random effect models and expressed as risk ratios (RR) with 95% confidence intervals (CIs). Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I(2) statistic). The Newcastle-Ottawa Scale assessed study quality. Clinicaltrials.gov NCT01608620. Eligibility criteria were met by 3 prospective cohorts (n = 37,375 men and 185,855 women) with 58,162 cases of hypertension observed over 2,502,357 person-years of follow-up. Median fructose intake was 5.7-6.0% total energy in the lowest quintile and 13.9-14.3% total energy in the highest quintile. Fructose intake was not associated with incident hypertension (RR = 1.02, 95% CI, 0.99-1.04), with no evidence of heterogeneity (I(2) = 0%, p = 0.59). Spline curve modeling showed a U-shaped relationship with a negative association at intakes ≤50th percentile (∼10% total energy) and a positive association at higher intakes. Total fructose intake was not associated with an increased risk of hypertension in 3 large prospective cohorts of U.S. men and women. | 25,144,126 | [
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Using testosterone and cortisol as biomarker for training individualization in elite basketball: a 4-year follow-up study. | The purpose of this study was to determine the responses of testosterone and cortisol, with special reference to playing positions, playing time (PT), and phase of the season. We performed a follow-up study during 4 consecutive seasons to investigate the effects of PT, positional role, and phase of the season on anabolic-catabolic biomarkers (plasma total testosterone -TT- and cortisol -C-) on 20 professional male basketball players (27.0 ± 4.2 years; 24.4 ± 1.2 kg·m). First blood samples were collected right after the off-season period and considered as baseline. Samples were taken periodically every 4-6 weeks, always after a 24- to 36-hour break after the last game played. Statistical procedures were nonparametric mainly. Hormonal status was playing position-dependent, power forward (PF) showed the lowest TT values (median ± interquartile range [IQR]; PF: 18.1 ± 4.9; nmol·L), and small forwards showed the highest ones of cortisol (0.55 ± 0.118 μmol·L). Players who played between 13 and 25 minutes per game showed the highest values of TT (22.8 ± 6.9 nmol·L) and TT/C (47.1 ± 21.2). March and April showed the most catabolic or stressed hormonal state (low TT/C values and high ones of cortisol) and that is necessary to take into account according to PT (>25-minute per game) and specific playing position. Monitoring plasma TT and cortisol is recommended to prevent excessive stress caused by professional basketball season requirements. | 25,144,130 | [
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Higher levels of sex chromosome heteromorphism are associated with markedly stronger reproductive isolation. | The two 'rules of speciation', Haldane's rule and the large X-effect, describe the genetic basis of postzygotic isolation, and have led to the realization that sex chromosomes play an important role in this process. However, a range of sex determination mechanisms exists in nature, not always involving sex chromosomes. Based on these 'rules of speciation', I test the hypothesis that the presence of sex chromosomes will contribute to a faster evolution of intrinsic postzygotic isolation. I show that taxa that do not have sex chromosomes evolve lower levels of postzygotic isolation than taxa with sex chromosomes, at a similar amount of genetic divergence. Taxa with young homomorphic sex chromosomes show an intermediate pattern compared to taxa with heteromorphic sex chromosomes and taxa without sex chromosomes. These results are consistent with predictions from the two 'rules of speciation', and emphasize the importance of sex chromosomes for the evolution of intrinsic postzygotic isolation. | 25,144,162 | [
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Reviewing effectiveness of ankle assessment techniques for use in robot-assisted therapy. | This article provides a comprehensive review of studies that investigated ankle assessment techniques to better understand those that can be used in the real-time monitoring of rehabilitation progress for implementation in conjunction with robot-assisted therapy. Seventy-six publications published between January 1980 and August 2013 were selected based on eight databases. They were divided into two main categories (16 qualitative and 60 quantitative studies): 13 goniometer studies, 18 dynamometer studies, and 29 studies about innovative techniques. A total of 465 subjects participated in the 29 quantitative studies of innovative measurement techniques that may potentially be integrated in a real-time monitoring device, of which 19 studies included less than 10 participants. Results show that qualitative ankle assessment methods are not suitable for real-time monitoring in robot-assisted therapy, though they are reliable for certain patients, while the quantitative methods show great potential. The majority of quantitative techniques are reliable in measuring ankle kinematics and kinetics but are usually available only for use in the sagittal plane. Limited studies determine kinematics and kinetics in all three planes (sagittal, transverse, and frontal) where motions of the ankle joint and the subtalar joint actually occur. | 25,144,166 | [
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Development of a progressive audiologic tinnitus management program for Veterans with tinnitus. | Tinnitus is the most prevalent service-connected disability awarded to Veterans. However, clinical protocols for management of tinnitus have been inconsistent across Department of Veterans Affairs (VA) medical centers. A study was funded to develop and pilot test a protocol to provide tinnitus services consistently across VA audiology clinics. Drawing on a series of prior VA and external research projects, a clinical model was formulated, supporting materials in multimedia were developed, and a pilot study was conducted. Five hierarchical levels of care were defined and labeled the Progressive Audiologic Tinnitus Management (PATM) model. The model facilitates access to medical services for tinnitus and includes detailed protocols for evaluation, education, and counseling of patients. Patients at each level of care have the option to "progress" to the next level of PATM if further services are required. Clinical procedures were defined for each level and materials were produced for audiologists and patients. The PATM model was then piloted with clinical patients at the James A. Haley Veterans' Hospital (JAHVH) in Tampa, Florida. Throughout the pilot study, feedback from patients and clinicians was carefully noted. Training materials for audiologists, incorporation of the protocol into clinic activities, and patient outcomes were evaluated. The model was implemented within the JAHVH Audiology Clinic and to assist Veterans with tinnitus management. The most notable finding was how little tinnitus-specific intervention was required for the majority of patients. This finding supports a clinical model that offers stepped-care ("progressive") levels of care until tinnitus management is achieved by the patient. | 25,144,174 | [
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Test-retest reliability and rater agreements of assessment of capacity for myoelectric control version 2.0. | The Assessment of Capacity for Myoelectric Control (ACMC) is an observation-based tool that evaluates ability to control a myoelectric prosthetic hand. Validity evidence led to ACMC version 2.0, but the test-retest reliability and minimal detectable change (MDC) of the ACMC have never been evaluated. Investigation of rater agreements in this version was also needed because it has new definitions in certain rating categories and items. Upper-limb prosthesis users (n = 25, 15 congenital, 10 acquired; mean age 27.5 yr) performed one standardized activity twice, 2 to 5 wk apart. Activity performances were videorecorded and assessed by two ACMC raters. Data were analyzed by weighted kappa, intraclass correlation coefficient (ICC), and Bland-Altman method. For test-retest reliability, weighted kappa agreements were fair to excellent (0.52 to 1.00), ICC2,1 was 0.94, and one user was located outside the limits of agreement in the Bland-Altman plot. MDC95 was less than or equal to 0.55 logits (1 rater) and 0.69 logits (2 raters). For interrater reliability, weighted kappa agreements were fair to excellent in both sessions (0.44 to 1.00), and ICC2,1 was 0.95 (test) and 0.92 (retest). Intrarater agreement (rater 1) was also excellent (ICC3,1 0.98). Evidence regarding the reliability of the ACMC is satisfactory and MDC95 can be used to indicate change. | 25,144,176 | [
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External validation of the simple clinical score and the HOTEL score, two scores for predicting short-term mortality after admission to an acute medical unit. | Clinical scores can be of aid to predict early mortality after admission to a medical admission unit. A developed scoring system needs to be externally validated to minimise the risk of the discriminatory power and calibration to be falsely elevated. We performed the present study with the objective of validating the Simple Clinical Score (SCS) and the HOTEL score, two existing risk stratification systems that predict mortality for medical patients based solely on clinical information, but not only vital signs. Pre-planned prospective observational cohort study. Danish 460-bed regional teaching hospital. We included 3046 consecutive patients from 2 October 2008 until 19 February 2009. 26 (0.9%) died within one calendar day and 196 (6.4%) died within 30 days. We calculated SCS for 1080 patients. We found an AUROC of 0.960 (95% confidence interval [CI], 0.932 to 0.988) for 24-hours mortality and 0.826 (95% CI, 0.774-0.879) for 30-day mortality, and goodness-of-fit test, χ(2) = 2.68 (10 degrees of freedom), P = 0.998 and χ(2) = 4.00, P = 0.947, respectively. We included 1470 patients when calculating the HOTEL score. Discriminatory power (AUROC) was 0.931 (95% CI, 0.901-0.962) for 24-hours mortality and goodness-of-fit test, χ(2) = 5.56 (10 degrees of freedom), P = 0.234. We find that both the SCS and HOTEL scores showed an excellent to outstanding ability in identifying patients at high risk of dying with good or acceptable precision. | 25,144,186 | [
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Differential sensitivity of Src-family kinases to activation by SH3 domain displacement. | Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo. | 25,144,189 | [
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Psychological stress exerts effects on pathogenesis of hepatitis B via type-1/type-2 cytokines shift toward type-2 cytokine response. | Psychological and physical stress has been demonstrated to have an impact on health through modulation of immune function. Despite high prevalence of stress among patients with hepatitis B virus (HBV) infection, little is known about whether and how stress exerts an effect on the course of hepatitis B. Eighty patients with chronic hepatitis B(CHB) completed the Perceived Stress Scale-10(PSS-10) and State-Trait Anxiety Inventory(STAI). Fresh whole blood was subject to flow cytometry for lymphocytes count. Plasma samples frozen at -80 °C were thawed for cytokines, alanine aminotransferase (ALT), and virus load. These patients were grouped into high or low perceived stress, state anxiety and trait anxiety groups according to the scale score. Sociodemographic, disease-specific characteristics, lymphocytes count and cytokines were compared. Firstly, a negative association between ALT and stress (t = -4.308; p = .000), state anxiety (t = -3.085; p = .003) and trait anxiety (t = -4.925; p = .000) were found. As ALT is a surrogate marker of hepatocytes injury, and liver injury is a consequence of immune responses. Next, we tested the relationship between stress/anxiety and lymphocytes. No statistical significance were found with respect to counts of total T cells, CD4+ T cell, CD8+ T cell, NK cell, and B cell count between high and low stress group. Type-2 cytokine interleukin-10 (IL-10) level was significantly higher in high stress group relative to lower counterpart (t = 6.538; p = 0.000), and type-1 cytokine interferon-gamma (IFN-γ) level shown a decreased tendency in high stress group (t = -1.702; p = 0.093). Finally, INF-γ:IL-10 ratio displayed significant decrease in high perceived stress(t = -4.606; p = 0.000), state anxiety(t = -5.126; p = 0.000) and trait anxiety(t = -4.670; p = 0.000) groups relative to low counterparts. Our data show stress is not related to the lymphocyte cells count in CHB patients, however, stress induces a shift in the type-1/type-2 cytokine balance towards a type-2 response, which implicated a role of psychological stress in the course of HBV related immune-pathogenesis. | 25,144,199 | [
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The role of emotion in musical improvisation: an analysis of structural features. | One of the primary functions of music is to convey emotion, yet how music accomplishes this task remains unclear. For example, simple correlations between mode (major vs. minor) and emotion (happy vs. sad) do not adequately explain the enormous range, subtlety or complexity of musically induced emotions. In this study, we examined the structural features of unconstrained musical improvisations generated by jazz pianists in response to emotional cues. We hypothesized that musicians would not utilize any universal rules to convey emotions, but would instead combine heterogeneous musical elements together in order to depict positive and negative emotions. Our findings demonstrate a lack of simple correspondence between emotions and musical features of spontaneous musical improvisation. While improvisations in response to positive emotional cues were more likely to be in major keys, have faster tempos, faster key press velocities and more staccato notes when compared to negative improvisations, there was a wide distribution for each emotion with components that directly violated these primary associations. The finding that musicians often combine disparate features together in order to convey emotion during improvisation suggests that structural diversity may be an essential feature of the ability of music to express a wide range of emotion. | 25,144,200 | [
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Patterns of shoulder imbalance in adolescent idiopathic scoliosis: a retrospective observational study. | Retrospective cohort study. To study the relationship between the proximal spine and shoulder levels in adolescent idiopathic scoliosis (AIS). It has been frequently observed that the shoulder levels do not correspond to the spinal curve direction in AIS. Eighty-five operated cases of AIS were analyzed retrospectively of which 69 were Lenke type I and II curves. Preoperative anteroposterior standing x-rays of the spine and clinical photographs were studied. T1 tilt and intercoracoid line (ICL) tilt and their mutual relationship were documented. The curve type (Lenke), magnitude, and direction of the proximal and main thoracic (PT and MT) curves were also noted. The shoulder level as depicted by the ICL showed 3 patterns-horizontal, left side elevated, or right side elevated. The T1-ICL relationship was either concordant or discordant. In the concordant case the T1 was tilted to the same side as the ICL; and vice versa in the discordant. The shoulder level was dependent on the MT curve if the ICL tilted to the same side as the MT curve and it was dependent on the PT curve if it tilted to the same side as the PT curve. This relationship appeared unrelated to curve type. Preoperative shoulder levels in AIS may be concordant with the T1 or discordant-each can have left or right shoulder elevation or balanced shoulders. Further, the shoulder might be MT dependent or PT dependent. Theoretically therefore, surgical balancing of the shoulder and upper instrumented vertebra placement should not depend only on the magnitude and stiffness of the PT curve. | 25,144,206 | [
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Myocardial and microvascular inflammation/infection in patients with HIV-associated pulmonary artery hypertension. | Right ventricle compromise affects survival of patients with HIV-associated pulmonary artery hypertension (PAH). Myocardial histology with viral assessment may clarify the mechanism of right ventricular deterioration and provide clues on PAH origin. Fifteen patients with HIV infection, PAH and right ventricular dysfunction underwent cardiac magnetic resonance, catheterization, coronary with ventricular angiography and biventricular endomyocardial biopsy. Endothelial expression of HLA-DR, ICAM-1, E-selectin and VCAM-1 was semi-quantitatively evaluated. PCR for HIV, hepatitis C virus, human herpes virus-6, human herpes virus-8, Epstein-Barr virus, adenovirus, cytomegalovirus, enterovirus, influenza A/B and parvovirus B19 was performed. In PCR-positive hearts, viral protein adenovirus-1 and TORDJI-22 were assessed by immunohistology. New York Heart Association class was 2.4 ± 0.5, mean pulmonary artery pressure 49.93 ± 10.15 mmHg and wedge pressure 9.5 ± 2.19 mmHg. Coronaries were normal with slow flow. Left ventricular and/or right ventricular micro-aneurysms were seen in eight patients. Cardiac magnetic resonance documented increased right ventricular end-diastolic volume with reduced ejection fraction, normal left ventricular end-diastolic volume and left ventricular ejection fraction. Subepicardial/mesocardial oedema and delayed enhancement in the inter-ventricular junction and/or left ventricular inferolateral wall was detected in eight patients. Histology showed active lymphocytic myocarditis in 12 patients, with microvasculitis in three. Endothelial adhesion molecules were over-expressed in all patients. PCR was positive in four patients for hepatitis C virus and in two for adenovirus, and viruses localized both in cardiomyocytes and endothelial cells. Inflammation/infection of myocardium and intramural vessels is detectable in patients with HIV-associated PAH. It may adversely affect right ventricular function and have a role in the compromised pulmonary circulation. | 25,144,217 | [
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Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay. | A gain-of-function mutation in the myeloproliferative leukemia virus (MPL) gene, which encodes the thrombopoietin receptor, has been identified in patients with essential thrombocythemia and primary myelofibrosis, subgroups of classic myeloproliferative neoplasms (MPNs). The presence of MPL gene mutations is a critical diagnostic criterion for these diseases. Here, we developed a rapid, simple, and cost-effective method of detecting two major MPL mutations, MPLW515L/K, in a single PCR assay; we termed this method DARMS (dual amplification refractory mutation system)-PCR. DARMS-PCR is designed to produce three different PCR products corresponding to MPLW515L, MPLW515K, and all MPL alleles. The amplicons are later detected and quantified using a capillary sequencer to determine the relative frequencies of the mutant and wild-type alleles. Applying DARMS-PCR to human specimens, we successfully identified MPL mutations in MPN patients, with the exception of patients bearing mutant allele frequencies below the detection limit (5%) of this method. The MPL mutant allele frequencies determined using DARMS-PCR correlated strongly with the values determined using deep sequencing. Thus, we demonstrated the potential of DARMS-PCR to detect MPL mutations and determine the allele frequencies in a timely and cost-effective manner. | 25,144,224 | [
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Distinct kinetics in the frequency of peripheral CD4+ T cells in patients with ulcerative colitis experiencing a flare during treatment with mesalazine or with a herbal preparation of myrrh, chamomile, and coffee charcoal. | We found the first evidence of the efficacy of a herbal treatment with myrrh, dry extract of chamomile flowers, and coffee charcoal for ulcerative colitis (UC). However, the impact of the herbal treatment on the CD4+ T-cell compartment, which is essential for both the induction of UC and the maintenance of tolerance in the gut, is not well understood. To analyze the frequency and functional phenotype of CD4+ T cells and of immune-suppressive CD4+CD25high regulatory T cells (Tregs) in healthy control subjects, patients with UC in remission, and patients with clinical flare of UC. Patients in clinical remission were treated with either mesalazine or the herbal preparation for 12 months. The frequencies of whole CD4+ T cells, CD4+CD25med effector T cells, and Tregs and the expression of Foxp3 within the CD4+CD25hig Tregs were determined by flow cytometry at 6 time points. We determined the suppressive capability of Tregs from healthy control subjects and from patients in remission or clinical flare. A total of 79 patients (42 women, 37 men; mean age, 48.5 years; 38 with clinical flare) and 5 healthy control subjects were included in the study. At baseline the frequencies of whole CD4+ T cells, CD4+CD25med effector cells, and Tregs did not differ between the two treatment groups and the healthy control subjects. In addition, patients with UC in sustained clinical remission showed no alteration from baseline after 1, 3, 6, 9, or 12 months of either treatment. In contrast, CD4+ T cells, CD4+CD25med effector T cells, and Tregs demonstrated distinctly different patterns at time points pre-flare and flare. The mesalazine group showed a continuous but not statistically significant increase from baseline to pre-flare and flare (p = ns). In the herbal treatment group, however, the percentage of the CD4+ T cells was lower at pre-flare than at baseline. This decrease was completely reversed after flare, when a significant increase was seen (CD4+CD25med pre-flare/flare p = 0.0461; CD4+CD25high baseline/flare p = 0.0269 and pre-flare/flare p = 0.0032). In contrast, no changes in the expression of Foxp3 cells were detected within the subsets of CD4+CD25high regulatory T cells. Of note, no alterations were detected in the suppressive capability of CD4+CD25high regulatory T cells isolated from the peripheral blood of healthy donors, from patients in remission, or from patients with clinical flare. In patients with UC experiencing acute flare, the CD4+ T compartment demonstrates a distinctly different pattern during treatment with myrrh, chamomile extract, and coffee charcoal than during treatment with mesalazine. These findings suggest an active repopulation of regulatory T cells during active disease. EU Clinical Trials Register 2007-007928-18/DE. | 25,144,293 | [
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Rapidly self-renewing human multipotent marrow stromal cells (hMSC) express sialyl Lewis X and actively adhere to arterial endothelium in a chick embryo model system. | There have been conflicting observations regarding the receptors utilized by human multipotent mesenchymal bone marrow stromal cells (hMSC) to adhere to endothelial cells (EC). To address the discrepancies, we performed experiments with cells prepared with a standardized, low-density protocol preserving a sub-population of small cells that are rapidly self-renewing. Sialyl Lewis X (SLeX) and α4 integrin expression were determined by flow cytometry. Fucosyltransferase expression was determined by quantitative realtime RT-PCR. Cell adhesion assays were carried out with a panel of endothelial cells from arteries, veins and the microvasculature in vitro. In vivo experiments were performed to determine single cell interactions in the chick embryo chorioallantoic membrane (CAM). The CAM is a well-characterized respiratory organ allowing for time-lapse image acquisition of large numbers of cells treated with blocking antibodies against adhesion molecules expressed on hMSC. hMSC expressed α4 integrin, SLeX and fucosyltransferase 4 and adhered to human EC from arteries, veins and the microvasculature under static conditions in vitro. In vivo, hMSC rolled on and adhered to arterioles in the chick embryo CAM, whereas control melanoma cells embolized. Inhibition of α4 integrin and/or SLeX with blocking antibodies reduced rolling and adhesion in arterioles and increased embolism of hMSC. The results demonstrated that rapidly self-renewing hMSC were retained in the CAM because they rolled on and adhered to respiratory arteriolar EC in an α4 integrin- and SLeX-dependent manner. It is therefore important to select cells based on their cell adhesion receptor profile as well as size depending on the intended target of the cell and the injection route. | 25,144,321 | [
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Positron emission tomography in CNS drug discovery and drug monitoring. | Molecular imaging methods such as positron emission tomography (PET) are increasingly involved in the development of new drugs. Using radioactive tracers as imaging probes, PET allows the determination of the pharmacokinetic and pharmacodynamic properties of a drug candidate, via recording target engagement, the pattern of distribution, and metabolism. Because of the noninvasive nature and quantitative end point obtainable by molecular imaging, it seems inherently suited for the examination of a pharmaceutical's behavior in the brain. Molecular imaging, most especially PET, can therefore be a valuable tool in CNS drug research. In this Perspective, we present the basic principles of PET, the importance of appropriate tracer selection, the impact of improved radiopharmaceutical chemistry in radiotracer development, and the different roles that PET can fulfill in CNS drug research. | 25,144,329 | [
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Simulation-based education and performance assessments for pediatric surgeons. | Education in the knowledge, skills, and attitudes necessary for a surgeon to perform at an expert level in the operating room, and beyond, must address all potential cognitive and technical performance gaps, professionalism and personal behaviors, and effective team communication. Educational strategies should also seek to replicate the stressors and distractions that might occur during a high-risk operation or critical care event. Finally, education cannot remain fixed in an apprenticeship model of "See one, do one, teach one," whereby patients are exposed to the risk of harm inherent to any learning curve. The majority of these educational goals can be achieved with the addition of simulation-based education (SBE) as a valuable adjunct to traditional training methods. This article will review relevant principles of SBE, explore currently available simulation-based educational tools for pediatric surgeons, and finally make projections for the future of SBE and performance assessments for pediatric surgeons. | 25,144,355 | [
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Pronator teres opposition transfer through Guyon's canal: a technique. | Restoration of thumb opposition in the setting of peripheral nerve or brachial plexus injury is critical to upper limb function. When commonly utilized opposition donors are unavailable for clinical use, the pronator teres represents a good and reliable tendon for restoration of thumb opposition. Here we describe our rational and technique for pronator teres opposition transfer using Guyon's canal as a pulley. | 25,144,357 | [
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Tracing the evolution of lineage-specific transcription factor binding sites in a birth-death framework. | Changes in cis-regulatory element composition that result in novel patterns of gene expression are thought to be a major contributor to the evolution of lineage-specific traits. Although transcription factor binding events show substantial variation across species, most computational approaches to study regulatory elements focus primarily upon highly conserved sites, and rely heavily upon multiple sequence alignments. However, sequence conservation based approaches have limited ability to detect lineage-specific elements that could contribute to species-specific traits. In this paper, we describe a novel framework that utilizes a birth-death model to trace the evolution of lineage-specific binding sites without relying on detailed base-by-base cross-species alignments. Our model was applied to analyze the evolution of binding sites based on the ChIP-seq data for six transcription factors (GATA1, SOX2, CTCF, MYC, MAX, ETS1) along the lineage toward human after human-mouse common ancestor. We estimate that a substantial fraction of binding sites (∼58-79% for each factor) in humans have origins since the divergence with mouse. Over 15% of all binding sites are unique to hominids. Such elements are often enriched near genes associated with specific pathways, and harbor more common SNPs than older binding sites in the human genome. These results support the ability of our method to identify lineage-specific regulatory elements and help understand their roles in shaping variation in gene regulation across species. | 25,144,359 | [
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Chemokine-like factor 1 promotes the migration of rat primary cortical neurons by the induction of actin polymerization. | Chemokine-like factor 1 (CKLF1), a newly cloned chemotactic cytokine, plays an essential role in immune cell migration. However, the potential role of CKLF1 in the cortical neuronal migration remains unclear. In the present research, by measuring the distance between the margin of brain slices and the leading population of migrating cells, we showed that the extent of cell migration was markedly enhanced in response to CKLF1 treatment, which was significantly inhibited by the simultaneous addition of anti-CKLF1 antibody. By immunofluorescence staining, it was found that CKLF1 induced actin polymerization in primary cerebral cortical neurons. By wound-healing assays, it was found that CKLF1 stimulated the migration of cortical neurons in a dose-dependent manner. In conclusion, our data suggest that CKLF1 promotes the migration of rat primary cerebral cortical neurons by the induction of actin polymerization. | 25,144,394 | [
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Resource-poor settings: response, recovery, and research: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. | Planning for mass critical care in resource-poor and constrained settings has been largely ignored, despite large, densely crowded populations who are prone to suffer disproportionately from natural disasters. As a result, disaster response has been suboptimal and in many instances hampered by lack of planning, education and training, information, and communication. The Resource-Poor Settings panel developed five key question domains; defining the term resource poor and using the traditional phases of the disaster cycle (mitigation/preparedness/response/recovery). Literature searches were conducted to identify evidence to answer the key questions in these areas. Given a lack of data on which to develop evidence-based recommendations, expert-opinion suggestions were developed, and consensus was achieved using a modified Delphi process. The five key questions were as follows: definition, capacity building and mitigation, what resources can we bring to bear to assist/surge, response, and reconstitution and recovery of host nation critical care capabilities. Addressing these led the panel to offer 33 suggestions. Because of the large number of suggestions, the results have been separated into two sections: part I, Infrastructure/Capacity in the accompanying article, and part II, Response/Recovery/Research in this article. A lack of rudimentary ICU resources and capacity to enhance services plagues resource-poor or constrained settings. Capacity building therefore entails preventative strategies and strengthening of primary health services. Assistance from other countries and organizations is often needed to mount a surge response. Moreover, the disengagement of these responding groups and host country recovery require active planning. Future improvements in all phases require active research activities. | 25,144,410 | [
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The invisible issue of organ laundering. | Global institutions, although suggesting measures to deter organ trafficking, reiterate the lack of official statistics about this illegal trade. In this article, we explore the reasons why organ trafficking remains unreported. We argue that the complex factors that perpetuate invisibility facilitate trafficked organs being "laundered" in the health care systems of the purchaser's country, hindering accurate estimation of the problem. The factors are as follows: (a) issues of globalization, jurisdiction, and law enforcement; (b) the power of health care professionals; (c) the reimbursement of transplantation costs abroad by insurers; (d) ambivalence of the victim status of the sellers; and (e) the buyers as vulnerable offenders. | 25,144,445 | [
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van der Waals radii of noble gases. | Consistent van der Waals radii are deduced for Ne-Xe, based on the noble gas···oxygen intermolecular distances found in gas phase structures. The set of radii proposed is shown to provide van der Waals distances for a wide variety of noble gas···element atom pairs that represent properly the distribution of distances both in the gas phase and in the solid state. Moreover, these radii show a smooth periodic trend down the group which is parallel to that shown by the halogens. | 25,144,450 | [
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Microcirculatory changes identified by photoacoustic microscopy in patients with complex regional pain syndrome type I after stellate ganglion blocks. | Complex regional pain syndrome (CRPS) is a chronic pain syndrome that causes intractable pain, disability, and poor quality of life for patients. The etiology and pathophysiology of CRPS are still poorly understood. Due to a lack of proper diagnostic tools, the prognosis of CRPS is primarily based on clinical observation. The objective of this work is to evaluate a new imaging modality, photoacoustic microscopy (PAM), for assisting diagnoses and monitoring the progress and treatment outcome of CRPS. Blood vasculature and oxygen saturation (sO₂) were imaged by PAM from eight adult patients with CRPS-1. Patients' hands and cuticles were imaged both before and after stellate ganglion block (SGB) for comparison. For all patients, both vascular structure and sO₂ could be assessed by PAM. In addition, more vessels and stronger signals were observed after SGB. The results show that PAM can help diagnose and monitor CRPS. | 25,144,451 | [
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LIN-3/EGF promotes the programmed cell death of specific cells in Caenorhabditis elegans by transcriptional activation of the pro-apoptotic gene egl-1. | Programmed cell death (PCD) is the physiological death of a cell mediated by an intracellular suicide program. Although key components of the PCD execution pathway have been identified, how PCD is regulated during development is poorly understood. Here, we report that the epidermal growth factor (EGF)-like ligand LIN-3 acts as an extrinsic signal to promote the death of specific cells in Caenorhabditis elegans. The loss of LIN-3 or its receptor, LET-23, reduced the death of these cells, while excess LIN-3 or LET-23 signaling resulted in an increase in cell deaths. Our molecular and genetic data support the model that the LIN-3 signal is transduced through LET-23 to activate the LET-60/RAS-MPK-1/ERK MAPK pathway and the downstream ETS domain-containing transcription factor LIN-1. LIN-1 binds to, and activates transcription of, the key pro-apoptotic gene egl-1, which leads to the death of specific cells. Our results provide the first evidence that EGF induces PCD at the whole organism level and reveal the molecular basis for the death-promoting function of LIN-3/EGF. In addition, the level of LIN-3/EGF signaling is important for the precise fine-tuning of the life-versus-death fate. Our data and the previous cell culture studies that say EGF triggers apoptosis in some cell lines suggest that the EGF-mediated modulation of PCD is likely conserved in C. elegans and humans. | 25,144,461 | [
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Magnon transistor for all-magnon data processing. | An attractive direction in next-generation information processing is the development of systems employing particles or quasiparticles other than electrons--ideally with low dissipation--as information carriers. One such candidate is the magnon: the quasiparticle associated with the eigen-excitations of magnetic materials known as spin waves. The realization of single-chip all-magnon information systems demands the development of circuits in which magnon currents can be manipulated by magnons themselves. Using a magnonic crystal--an artificial magnetic material--to enhance nonlinear magnon-magnon interactions, we have succeeded in the realization of magnon-by-magnon control, and the development of a magnon transistor. We present a proof of concept three-terminal device fabricated from an electrically insulating magnetic material. We demonstrate that the density of magnons flowing from the transistor's source to its drain can be decreased three orders of magnitude by the injection of magnons into the transistor's gate. | 25,144,479 | [
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Redefining "charge nurse" within the front line. | Don't overlook the importance of charge nurses. Learn how one organization redefined the role and strengthened these leaders, increasing patient and staff satisfaction. | 25,144,488 | [
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Hydrotropy: monomer-micelle equilibrium and minimum hydrotrope concentration. | Drug molecules with low aqueous solubility can be solubilized by a class of cosolvents, known as hydrotropes. Their action has often been explained by an analogy with micelle formation, which exhibits critical micelle concentration (CMC). Indeed, hydrotropes also exhibit "minimum hydrotrope concentration" (MHC), a threshold concentration for solubilization. However, MHC is observed even for nonaggregating monomeric hydrotropes (such as urea); this raises questions over the validity of this analogy. Here we clarify the effect of micellization on hydrotropy, as well as the origin of MHC when micellization is not accompanied. On the basis of the rigorous Kirkwood-Buff (KB) theory of solutions, we show that (i) micellar hydrotropy is explained also from preferential drug-hydrotrope interaction; (ii) yet micelle formation reduces solubilization effeciency per hydrotrope molecule; (iii) MHC is caused by hydrotrope-hydrotrope self-association induced by the solute (drug) molecule; and (iv) MHC is prevented by hydrotrope self-aggregation in the bulk solution. We thus need a departure from the traditional view; the structure of hydrotrope-water mixture around the drug molecule, not the structure of the aqueous hydrotrope solutions in the bulk phase, is the true key toward understanding the origin of MHC. | 25,144,510 | [
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Plasma exchange in antineutrophil cytoplasm antibody-associated vasculitis. | This article reviews the use of plasma exchange for the treatment of antineutrophil cytoplasm antibody-associated vasculitis (AAV) with a focus on current controversies and knowledge gaps. Experimental evidence suggesting that antineutrophil cytoplasm antibodies are pathogenic continues to evolve and support the theory that rapid removal of antineutrophil cytoplasm antibody with plasma exchange may be beneficial. Although early, small trials of plasma exchange in rapidly progressive glomerulonephritis and vasculitis suggested that plasma exchange may improve a patient's potential for renal recovery, more recent analyses have called the net benefit of plasma exchange into question. Furthermore, there is uncertainty as to whether plasma exchange is beneficial to patients with particular organ manifestations of their AAV (e.g., lung hemorrhage). Whether plasma exchange should be used routinely in antineutrophil cytoplasm antibody-associated vasculitis, in patients with certain manifestations or severity of disease only, or not at all, remains unclear. Given that plasma exchange is expensive and invasive, further research to resolve these uncertainties is required. | 25,144,513 | [
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New Kagome metal Sc₃Mn₃Al₇Si₅ and its gallium-doped analogues: synthesis, crystal structure, and physical properties. | We report the synthesis, crystal structure, and basic properties of the new intermetallic compound Sc3Mn3Al7Si5. The structure of the compound was established by single-crystal X-ray diffraction, and it crystallizes with a hexagonal structure (Sc3Ni11Si4 type) with Mn atoms forming the Kagome nets. The dc magnetic susceptibility measurements reveal a Curie-Weiss moment of ~0.51 μ(B)/Mn; however, no magnetic order is found for temperatures as low as 1.8 K. Electrical resistivity and heat capacity measurements show that this compound is definitively metallic, with a relatively large specific heat Sommerfeld coefficient, indicating strong electronic correlations. Intriguingly, these features have revealed Sc3Mn3Al7Si5 as a possible quantum spin liquid. With chemical and lattice disorder introduced by doping, a spin liquid to spin glass transition is observed in the highest Ga-doped compounds. The roles of the geometrically frustrated structure and Mn-ligand hybridization in the magnetism of the title compounds are also discussed. | 25,144,523 | [
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Personal trust increases cooperation beyond general trust. | In this paper we present a new methodology which, while allowing for anonymous interaction, it also makes possible to compare decisions of cooperating or defecting when playing games within a group, according to whether or not players personally trust each other. The design thus goes beyond standard approaches to the role of trust in fostering cooperation, which is restricted to general trust. It also allows considering the role of the topology of the social network involved may play in the level of cooperation found. The results of this work support the idea that personal trust promotes cooperation beyond the level of general trust. We also found that this effect carries over to the whole group, making it more cohesive, but that higher levels of cohesion rely on a particular topology. As a conclusion, we hypothesize that personal trust is a psychological mechanism evolved to make human social life possible in the small groups our ancestors lived in, and that this mechanism persists and plays a role in sustaining cooperation and social cohesion. | 25,144,539 | [
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Synthesis of 1-(2,3-dihydrobenzofuran-3-yl)-methanesulfonohydrazides through insertion of sulfur dioxide. | A three-component reaction of 2-(allyloxy)anilines, sulfur dioxide and hydrazines under mild conditions is developed, which gives rise to 1-(2,3-dihydrobenzofuran-3-yl)-methanesulfonohydrazides in good yields. This radical process involves an intramolecular 5-exo-cyclization and insertion of sulfur dioxide. | 25,144,558 | [
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Functional specialization among members of Knickkopf family of proteins in insect cuticle organization. | Our recent study on the functional analysis of the Knickkopf protein from T. castaneum (TcKnk), indicated a novel role for this protein in protection of chitin from degradation by chitinases. Knk is also required for the laminar organization of chitin in the procuticle. During a bioinformatics search using this protein sequence as the query, we discovered the existence of a small family of three Knk-like genes (including the prototypical TcKnk) in the T. castaneum genome as well as in all insects with completed genome assemblies. The two additional Knk-like genes have been named TcKnk2 and TcKnk3. Further complexity arises as a result of alternative splicing and alternative polyadenylation of transcripts of TcKnk3, leading to the production of three transcripts (and by inference, three proteins) from this gene. These transcripts are named TcKnk3-Full Length (TcKnk3-FL), TcKnk3-5' and TcKnk3-3'. All three Knk-family genes appear to have essential and non-redundant functions. RNAi for TcKnk led to developmental arrest at every molt, while down-regulation of either TcKnk2 or one of the three TcKnk3 transcripts (TcKnk3-3') resulted in specific molting arrest only at the pharate adult stage. All three Knk genes appear to influence the total chitin content at the pharate adult stage, but to variable extents. While TcKnk contributes mostly to the stability and laminar organization of chitin in the elytral and body wall procuticles, proteins encoded by TcKnk2 and TcKnk3-3' transcripts appear to be required for the integrity of the body wall denticles and tracheal taenidia, but not the elytral and body wall procuticles. Thus, the three members of the Knk-family of proteins perform different essential functions in cuticle formation at different developmental stages and in different parts of the insect anatomy. | 25,144,557 | [
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UK audit of glomerular filtration rate measurement from plasma sampling in 2013. | An audit was carried out into UK glomerular filtration rate (GFR) calculation. The results were compared with an identical 2001 audit. Participants used their routine method to calculate GFR for 20 data sets (four plasma samples) in millilitres per minute and also the GFR normalized for body surface area. Some unsound data sets were included to analyse the applied quality control (QC) methods. Variability between centres was assessed for each data set, compared with the national median and a reference value calculated using the method recommended in the British Nuclear Medicine Society guidelines. The influence of the number of samples on variability was studied. Supplementary data were requested on workload and methodology. The 59 returns showed widespread standardization. The applied early exponential clearance correction was the main contributor to the observed variability. These corrections were applied by 97% of centres (50% - 2001) with 80% using the recommended averaged Brochner-Mortenson correction. Approximately 75% applied the recommended Haycock body surface area formula for adults (78% for children). The effect of the number of samples used was not significant. There was wide variability in the applied QC techniques, especially in terms of the use of the volume of distribution. The widespread adoption of the guidelines has harmonized national GFR calculation compared with the previous audit. Further standardization could further reduce variability. This audit has highlighted the need to address the national standardization of QC methods. Radionuclide techniques are confirmed as the preferred method for GFR measurement when an unequivocal result is required. | 25,144,565 | [
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"The uncertainty is what is driving me crazy": the tripartite model of uncertainty in the adolescent and young adult cancer context. | Building on scholarship indicating that uncertainty is a fundamental component of the cancer experience, this study focuses on an understudied population: adolescents and young adults (AYAs) with cancer. Because AYAs' health outcomes lag behind those of older and younger people with cancer, scholars have recommended that the subjective experiences of AYAs be better understood. Using the tripartite model of uncertainty sources as a guiding framework, we analyzed naturally occurring messages from an online discussion forum for AYA cancer survivors. The majority of messages communicating uncertainty expressed medical uncertainty regarding the complexities of understanding treatment options and sequelae. Results indicated that several overarching areas of AYA uncertainty correspond to themes reported by other cancer populations, but that some distinctive concerns arise amid the normative complexities of late adolescence and young adulthood. | 25,144,578 | [
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Longitudinal relationships among visual acuity, daily functional status, and mortality: the Salisbury Eye Evaluation Study. | Determination of the mechanisms by which visual loss increases mortality risk is important for developing interventional strategies. To evaluate the direct and indirect effects of loss of visual acuity (VA) on mortality risk through functional status changes among aging adults. Prospective longitudinal study of a population-based sample of 2520 noninstitutionalized adults aged 65 to 84 years from September 16, 1993, through July 26, 2003, in the greater Salisbury area of Maryland. Participants underwent reassessment 2, 6, and 8 years after baseline. Mortality status was ascertained from linkage with the National Death Index through 2009. Results of VA testing and self-reported functional status based on activities of daily living (ADL) and instrumental ADL (IADL). Mortality. Worse VA levels at baseline were associated with an increased the risk for mortality (hazard ratio [HR], 1.16 [95% CI, 1.04-1.28]; P < .01) through their effect on lower IADL levels at baseline. Declines in VA over time were associated with increased mortality risk (HR, 1.78 [95% CI, 1.27-2.51]; P < .001) by way of decreasing IADL levels over time. Participants experiencing the mean linear decline in VA of 1 letter on the Early Treatment Diabetic Retinopathy Study acuity chart per year are expected to have a 16% increase in mortality risk during the 8-year study exclusively through associated declines in IADL levels. In this longitudinal study of older adults, VA loss adversely affected IADL levels, which subsequently increased the risk for mortality. Prevention of disabling ocular conditions, treatment of correctable visual impairment, and interventions designed to prevent the effect of visual impairment on IADL declines may all reduce mortality risk in aging adults. | 25,144,579 | [
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Women's center staff perceptions of the campus climate on sexual violence. | Sexual assault is a major public health problem disproportionately affecting women on college and university campuses. As sexual assault is often unreported, survivors may not have the access to resources and services that are helpful in healing. Campus-based women's centers provide a comfortable place and resource to address women's issues on campus. Individuals who work in these centers have open communication channels with students and a role in the administrative structure that may provide a unique understanding of survivors, the student environment, and the institutional context regarding sexual assault. The purpose of this study was to understand the perceptions of campus-based women's center staff on college and university campuses, specifically regarding campus-based responses to sexual assault. Participants responded electronically to six open-ended survey questions. Data were analyzed using a qualitative content analysis approach to identify key themes present within the data. Key concepts identified included respect, trust, confidentiality, trained professionals, and comprehensive and consistent response. The findings provide an early description of the perceptions of staff in campus-based women's centers related to prevention, reporting, and response to sexual violence on campuses and can be used to inform campus policies and practices as well as forensic and college-based nursing practice. | 25,144,584 | [
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Victimization and perpetration of sexual violence in college-aged men and women. | Sexual violence is a significant public health issue on college campuses. Much of the research to date has focused on sexual violence victimization with less data on perpetration of sexual violence. This analysis describes sexual violence victimization and perpetration experiences in a sample of college students. We sought to recruit college students attending three universities in the United States. A cross-sectional survey design was used to contact students through e-mail or voluntary gatherings. Each participant completed a questionnaire focused on experiences of sexual violence. A total of 1,978 students consented to participate in the study with 1,829 completing the questions related to victimization experiences and 1,479 completing the questions related to perpetration experiences. Thirty-eight percent (n = 700) of the sample (men and women) reported sexual violence victimization. Victimization among women and men was 42.6% and 28.7%, respectively. Almost 6% (n = 100) of the sample reported sexual violence perpetration. Men reported a higher rate of perpetration, 14.5% (n = 60), compared to women, 3.8% (n = 40). This study provides data on both victimization and perpetration experiences of college students. Both college men and women reported experiences of being victimized as well as perpetrating sexual violence. Understanding victimization and perpetration on college campuses will increase awareness, thus piercing the silence, of unwanted sexual experiences and help move college campuses toward a response. | 25,144,586 | [
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Tuning electronic and magnetic properties of silicene with magnetic superhalogens. | Due to its compatibility with the well-developed Si-based semiconductor industry, silicene has attracted considerable attention. Using density functional theory we show for the first time that the recently synthesized superhalogen MnCl3 can be used to tune the electronic and magnetic properties of silicene, from semi-metallic to semiconducting with a wide range of band gaps, as well as from nonmagnetic to ferromagnetic (or antiferromagnetic) by changing the coverage of the superhalogen molecules. The electronic properties can be further modulated when a superhalogen and a halogen are used synergistically. The present study indicates that because of the large electron affinity and rich structural diversity superhalogen molecules have advantages over the conventional halogen atoms in modulating the material properties of silicene. | 25,144,623 | [
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Remission after potassium iodide therapy in patients with Graves' hyperthyroidism exhibiting thionamide-associated side effects. | Thionamides have various side effects. The effectiveness of potassium iodide (KI) was evaluated in hyperthyroid patients who experienced side effects to thionamides. An observational study was conducted at an academic medical center. Among 1388 patients with Graves' hyperthyroidism treated with thionamides, 204 (14.7%) exhibited side effects, and 44 were treated with KI and followed for 17.6 (median; range, 8.6-28.4) years. The primary endpoint was the initial response to KI, and the secondary endpoint was the long-term prognosis. The conditions of 29 (65.9%) of the 44 patients were well controlled with KI alone (10-400 mg/d) (A group), and 17 (38.6%) patients went into remission after 7.4 (1.9-23.0) years. The conditions of 15 (34.1%) patients were not controlled with KI alone (B group), even at a high dose (100-750 mg/d), but seven patients (15.9%) were controlled with a combination of KI and low-dose thionamides, resulting in remission after 7.2 (2.8-10.8) years. The initial parameters did not predict the response to KI or long-term prognosis. However, remission occurred in 70.8% of the patients treated with less than 200 mg of KI, compared with 35.0% of the patients who required 200 mg or more of KI (P < .05). Among hyperthyroid patients with thionamide-associated side effects, KI therapy was effective in two-thirds of cases, and about 40% of the patients experienced remission after KI therapy alone. The chance of remission was small among the patients refractory to KI. | 25,144,628 | [
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A simple algorithm for treating horizontal benign paroxysmal positional vertigo. | Horizontal benign paroxysmal positional vertigo (H-BPPV) is more difficult to successfully treat than posterior benign paroxysmal positional vertigo (P-BPPV) because of the diverse mechanisms required. We developed a simple, rapid, and effective treatment algorithm for treating all subtypes of H-BPPV in an ear, nose, and throat (ENT) outpatient department. Four hundred ninety patients with BPPV receiving outpatient treatment at Mackay Memorial Hospital were investigated. Among the 490 patients, 86 (17.6%; 86/490) were diagnosed as having H-BPPV variants using the McClure-Pagnini test. Fifty-four patients were female, and 32 were male; they ranged in age from 18 to 92 years (mean age, 56.2 yr). Among the 86 H-BPPV patients, 74.4% (64/86) were hypothesized to have canalithiasis, 20.9% (18/86) were hypothesized to have cupulolithiasis-utricle type (Cup-U), and 4.7% (4/86) were hypothesized to have the cupulolithiasis-cupula type (Cup-C). The primary treatment maneuver was the forced prolonged position (FPP). For 3 patients exhibiting refractory symptoms, we introduced the Gufoni maneuver. The total average success rate of treatment was 96%. We concluded that for H-BPPV patients with initial geotropic nystagmus, the FPP alone yielded an excellent treatment-control rate, and the barbecue-rotation maneuver was unnecessary. However, observing the nystagmus transformation of apogeotropic patients was necessary before administering treatment. For cupulolithiasis patients with the apogeotropic variant who did not respond to FPP treatment alone, we determined that the Gufoni maneuver was necessary as well. | 25,144,642 | [
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Relationship between bone mineral density and a 10-year risk for coronary artery disease in a healthy Korean population: the Korea National Health and Nutrition Examination Survey 2008-2010. | Bone mineral density (BMD) is associated with atherosclerosis and vascular calcification. If BMD is related independently to the risk of coronary heart disease (CHD), BMD could play an important role in CHD risk prediction. We assessed the hypothesis that BMD is related independently to the risk of CHD. We used data from the fourth and fifth Korea National Health and Nutrition Examination Surveys. The study sample included men and women aged 20-79 years, who did not have myocardial infarction, angina pectoris, stroke, or diabetes mellitus. We evaluated the relationship between BMD and the Framingham risk score for each sex. In the male population, femur neck BMD [coefficient=-2.167, 95% confidence interval (CI) -3.385 to -0.950, P=0.001] and lumbar spine BMD (coefficient=-1.539, 95% CI -2.546 to -0.532, P=0.003) showed an inverse correlation with the Framingham risk score after adjusting for covariates. In the female population, the relationship between BMD parameters and the Framingham risk score was not significant after adjusting for covariates. In the male population, those with femur neck BMD values in the first quartile had greater odds of a 10-year risk greater than or equal to 10% for CHD compared with those in the fourth quartile (odds ratio=1.942, 95% CI 1.315-2.869, P<0.001). BMD was correlated inversely with the 10-year risk for CHD in the healthy male population. This result suggests that in the male population, measurement of BMD could be useful for prediction of the risk of CHD. | 25,144,671 | [
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Feature selection for the identification of antitumor compounds in the alcohol total extracts of Curcuma longa. | Antitumor activity has been reported for turmeric, the dried rhizome of Curcuma longa. This study proposes a new feature selection method for the identification of the antitumor compounds in turmeric total extracts. The chemical composition of turmeric total extracts was analyzed by gas chromatography-mass spectrometry (21 ingredients) and high-performance liquid chromatography-mass spectrometry (22 ingredients), and their cytotoxicity was detected through an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay against HeLa cells. A support vector machine for regression and a generalized regression neural network were used to research the composition-activity relationship and were later combined with the mean impact value to identify the antitumor compounds. The results showed that six volatile constituents (three terpenes and three ketones) and seven nonvolatile constituents (five curcuminoids and two unknown ingredients) with high absolute mean impact values exhibited a significant correlation with the cytotoxicity against HeLa cells. With the exception of the two unknown ingredients, the identified 11 constituents have been reported to exhibit cytotoxicity. This finding indicates that the feature selection method may be a supplementary tool for the identification of active compounds from herbs. | 25,144,675 | [
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Factors associated with perceived health among Korean adolescents. | This study examined the influences of personal, social, and environmental-structural factors on the perceived health of Korean adolescents. Using a two-stage generalized hierarchical logistic linear multilevel model, this study found that general high school enrollment, younger age, normal weight, and frequent exercise increased the likelihood of a positive self-perception of health. Higher levels of parental concern and quality of school life also contributed to the likelihood of students perceiving themselves as healthy. In contrast, psychological symptoms and negative self-esteem decreased the likelihood that students perceived themselves as healthy. The results provide implications for disease prevention and health promotion programs. | 25,144,695 | [
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A model-based approach for identifying signatures of ancient balancing selection in genetic data. | While much effort has focused on detecting positive and negative directional selection in the human genome, relatively little work has been devoted to balancing selection. This lack of attention is likely due to the paucity of sophisticated methods for identifying sites under balancing selection. Here we develop two composite likelihood ratio tests for detecting balancing selection. Using simulations, we show that these methods outperform competing methods under a variety of assumptions and demographic models. We apply the new methods to whole-genome human data, and find a number of previously-identified loci with strong evidence of balancing selection, including several HLA genes. Additionally, we find evidence for many novel candidates, the strongest of which is FANK1, an imprinted gene that suppresses apoptosis, is expressed during meiosis in males, and displays marginal signs of segregation distortion. We hypothesize that balancing selection acts on this locus to stabilize the segregation distortion and negative fitness effects of the distorter allele. Thus, our methods are able to reproduce many previously-hypothesized signals of balancing selection, as well as discover novel interesting candidates. | 25,144,706 | [
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The Par-PrkC polarity complex is required for cilia growth in zebrafish photoreceptors. | Specification and development of the apical membrane in epithelial cells requires the function of polarity proteins, including Pard3 and an atypical protein kinase C (PrkC). Many epithelial cells possess microtubule-based organelles, known as cilia, that project from their apical surface and the membrane surrounding the cilium is contiguous with the apical cell membrane. Although cilia formation in cultured cells required Pard3, the in vivo requirement for Pard3 in cilia development remains unknown. The vertebrate photoreceptor outer segment represents a highly specialized cilia structure in which to identify factors necessary for apical and ciliary membrane formation. Pard3 and PrkC localized to distinct domains within vertebrate photoreceptors. Using partial morpholino knockdown, photo-morpholinos, and pharmacological approaches, the function of Pard3 and PrkC were found to be required for the formation of both the apical and ciliary membrane of vertebrate photoreceptors. Inhibition of Pard3 or PrkC activity significantly reduced the size of photoreceptor outer segments and resulted in mislocalization of rhodopsin. Suppression of Pard3 or PrkC also led to a reduction in cilia size and cilia number in Kupffer's Vesicle, which resulted in left-right asymmetry defects. Thus, the Par-PrkC complex functions in cilia formation in vivo and this likely reflects a general role in specifying non-ciliary and ciliary compartments of the apical domain. | 25,144,710 | [
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System-level planning, coordination, and communication: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. | System-level planning involves uniting hospitals and health systems, local/regional government agencies, emergency medical services, and other health-care entities involved in coordinating and enabling care in a major disaster. We reviewed the literature and sought expert opinions concerning system-level planning and engagement for mass critical care due to disasters or pandemics and offer suggestions for system-planning, coordination, communication, and response. The suggestions in this chapter are important for all of those involved in a pandemic or disaster with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. The American College of Chest Physicians (CHEST) consensus statement development process was followed in developing suggestions. Task Force members met in person to develop nine key questions believed to be most relevant for system-planning, coordination, and communication. A systematic literature review was then performed for relevant articles and documents, reports, and other publications reported since 1993. No studies of sufficient quality were identified upon which to make evidence-based recommendations. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. Suggestions were developed and grouped according to the following thematic elements: (1) national government support of health-care coalitions/regional health authorities (HC/RHAs), (2) teamwork within HC/RHAs, (3) system-level communication, (4) system-level surge capacity and capability, (5) pediatric patients and special populations, (6) HC/RHAs and networks, (7) models of advanced regional care systems, and (8) the use of simulation for preparedness and planning. System-level planning is essential to provide care for large numbers of critically ill patients because of disaster or pandemic. It also entails a departure from the routine, independent system and involves all levels from health-care institutions to regional health authorities. National government support is critical, as are robust communication systems and advanced planning supported by realistic exercises. | 25,144,713 | [
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0.00031423... |
Mir-509-5p joins the Mdm2/p53 feedback loop and regulates cancer cell growth. | Although the Mdm2/p53 interaction has been well documented, it is not clear whether there are new microRNAs participating in this regulatory network. Here, we provide evidence that miR-509-5p, which is downregulated in a subset of newly diagnosed cervical cancer and hepatocellular carcinoma tissues compared with the adjacent nontumor tissue, can be activated by p53 through binding the promoter of miR-509-5p and it suppresses the growth and invasion/migration of cervical cancer and hepatoma cells by regulating apoptosis and the G1/S-phase transition of cell cycle. Furthermore, Mdm2 was identified to be a target of miR-509-5p by targeting its 3'-UTR. Restoration of Mdm2 abrogated the cell phenotypes induced by miR-509-5p. Moreover, ectopic expression of miR-509-5p in HeLa and QGY-7703 cells repressed the expression of Mdm2, subsequently enhancing its p53-activating effects. These results suggest that miR-509-5p is a new regulator of Mdm2/p53 pathway and may play a key role in cancer development. | 25,144,722 | [
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0.... |
Circulating mucosal associated invariant T cells are activated in Vibrio cholerae O1 infection and associated with lipopolysaccharide antibody responses. | Mucosal Associated Invariant T (MAIT) cells are innate-like T cells found in abundance in the intestinal mucosa, and are thought to play a role in bridging the innate-adaptive interface. We measured MAIT cell frequencies and antibody responses in blood from patients presenting with culture-confirmed severe cholera to a hospital in Dhaka, Bangladesh at days 2, 7, 30, and 90 of illness. We found that MAIT (CD3+CD4-CD161hiVα7.2+) cells were maximally activated at day 7 after onset of cholera. In adult patients, MAIT frequencies did not change over time, whereas in child patients, MAITs were significantly decreased at day 7, and this decrease persisted to day 90. Fold changes in MAIT frequency correlated with increases in LPS IgA and IgG, but not LPS IgM nor antibody responses to cholera toxin B subunit. In the acute phase of cholera, MAIT cells are activated, depleted from the periphery, and as part of the innate response against V. cholerae infection, are possibly involved in mechanisms underlying class switching of antibody responses to T cell-independent antigens. | 25,144,724 | [
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Rational design of a fusion protein to exhibit disulfide-mediated logic gate behavior. | Synthetic cellular logic gates are primarily built from gene circuits owing to their inherent modularity. Single proteins can also possess logic gate functions and offer the potential to be simpler, quicker, and less dependent on cellular resources than gene circuits. However, the design of protein logic gates that are modular and integrate with other cellular components is a considerable challenge. As a step toward addressing this challenge, we describe the design, construction, and characterization of AND, ORN, and YES logic gates built by introducing disulfide bonds into RG13, a fusion of maltose binding protein and TEM-1 β-lactamase for which maltose is an allosteric activator of enzyme activity. We rationally designed these disulfide bonds to manipulate RG13's allosteric regulation mechanism such that the gating had maltose and reducing agents as input signals, and the gates could be toggled between different gating functions using redox agents, although some gates performed suboptimally. | 25,144,732 | [
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0.05... |
Structural and biochemical characterization of the Cop9 signalosome CSN5/CSN6 heterodimer. | The Cop9 signalosome complex (CSN) regulates the functional cycle of the major E3 ubiquitin ligase family, the cullin RING E3 ubiquitin ligases (CRLs). Activated CRLs are covalently modified by the ubiquitin-like protein Nedd8 (neural precursor cell expressed developmentally down-regulated protein 8). CSN serves an essential role in myriad cellular processes by reversing this modification through the isopeptidase activity of its CSN5 subunit. CSN5 alone is inactive due to an auto-inhibited conformation of its catalytic domain. Here we report the molecular basis of CSN5 catalytic domain activation and unravel a molecular hierarchy in CSN deneddylation activity. The association of CSN5 and CSN6 MPN (for Mpr1/Pad1 N-terminal) domains activates its isopeptidase activity. The CSN5/CSN6 module, however, is inefficient in CRL deneddylation, indicating a requirement of further elements in this reaction such as other CSN subunits. A hybrid molecular model of CSN5/CSN6 provides a structural framework to explain these functional observations. Docking this model into a published CSN electron density map and using distance constraints obtained from cross-linking coupled to mass-spectrometry, we find that the C-termini of the CSN subunits could form a helical bundle in the centre of the structure. They likely play a key scaffolding role in the spatial organization of CSN and precise positioning of the dimeric MPN catalytic core. | 25,144,743 | [
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0.1803267,... |
Immunization with Hexon modified adenoviral vectors integrated with gp83 epitope provides protection against Trypanosoma cruzi infection. | Trypanosoma cruzi is the causative agent of Chagas disease. Chagas disease is an endemic infection that affects over 8 million people throughout Latin America and now has become a global challenge. The current pharmacological treatment of patients is unsuccessful in most cases, highly toxic, and no vaccines are available. The results of inadequate treatment could lead to heart failure resulting in death. Therefore, a vaccine that elicits neutralizing antibodies mediated by cell-mediated immune responses and protection against Chagas disease is necessary. The "antigen capsid-incorporation" strategy is based upon the display of the T. cruzi epitope as an integral component of the adenovirus' capsid rather than an encoded transgene. This strategy is predicted to induce a robust humoral immune response to the presented antigen, similar to the response provoked by native Ad capsid proteins. The antigen chosen was T. cruzi gp83, a ligand that is used by T. cruzi to attach to host cells to initiate infection. The gp83 epitope, recognized by the neutralizing MAb 4A4, along with His6 were incorporated into the Ad serotype 5 (Ad5) vector to generate the vector Ad5-HVR1-gp83-18 (Ad5-gp83). This vector was evaluated by molecular and immunological analyses. Vectors were injected to elicit immune responses against gp83 in mouse models. Our findings indicate that mice immunized with the vector Ad5-gp83 and challenged with a lethal dose of T. cruzi trypomastigotes confer strong immunoprotection with significant reduction in parasitemia levels, increased survival rate and induction of neutralizing antibodies. This data demonstrates that immunization with adenovirus containing capsid-incorporated T. cruzi antigen elicits a significant anti-gp83-specific response in two different mouse models, and protection against T. cruzi infection by eliciting neutralizing antibodies mediated by cell-mediated immune responses, as evidenced by the production of several Ig isotypes. Taken together, these novel results show that the recombinant Ad5 presenting T. cruzi gp83 antigen is a useful candidate for the development of a vaccine against Chagas disease. | 25,144,771 | [
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The MAP kinase p38 is part of Drosophila melanogaster's circadian clock. | All organisms have to adapt to acute as well as to regularly occurring changes in the environment. To deal with these major challenges organisms evolved two fundamental mechanisms: the p38 mitogen-activated protein kinase (MAPK) pathway, a major stress pathway for signaling stressful events, and circadian clocks to prepare for the daily environmental changes. Both systems respond sensitively to light. Recent studies in vertebrates and fungi indicate that p38 is involved in light-signaling to the circadian clock providing an interesting link between stress-induced and regularly rhythmic adaptations of animals to the environment, but the molecular and cellular mechanisms remained largely unknown. Here, we demonstrate by immunocytochemical means that p38 is expressed in Drosophila melanogaster's clock neurons and that it is activated in a clock-dependent manner. Surprisingly, we found that p38 is most active under darkness and, besides its circadian activation, additionally gets inactivated by light. Moreover, locomotor activity recordings revealed that p38 is essential for a wild-type timing of evening activity and for maintaining ∼ 24 h behavioral rhythms under constant darkness: flies with reduced p38 activity in clock neurons, delayed evening activity and lengthened the period of their free-running rhythms. Furthermore, nuclear translocation of the clock protein Period was significantly delayed on the expression of a dominant-negative form of p38b in Drosophila's most important clock neurons. Western Blots revealed that p38 affects the phosphorylation degree of Period, what is likely the reason for its effects on nuclear entry of Period. In vitro kinase assays confirmed our Western Blot results and point to p38 as a potential "clock kinase" phosphorylating Period. Taken together, our findings indicate that the p38 MAP Kinase is an integral component of the core circadian clock of Drosophila in addition to playing a role in stress-input pathways. | 25,144,774 | [
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0.1861166,
0.009283439,... |
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