Regulation of fibrillin carboxy-terminal furin processing by N-glycosylation, and association of amino- and carboxy-terminal sequences.
The molecular mechanisms of fibrillin assembly into microfibrils are poorly understood. In this study, we investigated human fibrillin-1 carboxy-terminal processing and assembly using a recombinant approach. Processing of carboxy-terminal fibrillin-1 was strongly influenced by N-glycosylation at the site immediately downstream of the furin site, and by association with calreticulin. The carboxy terminus of fibrillin-2 underwent less efficient processing than carboxy-terminal fibrillin-1 under identical conditions. Size fractionation of the amino-terminal region of fibrillin-1, and of unprocessed and furin-processed carboxy-terminal region of fibrillin-1, revealed that the amino terminus formed abundant disulphide-bonded aggregates. Some association of unprocessed carboxy-terminal fibrillin-1 was also apparent, but processed carboxy-terminal sequences remained monomeric unless amino-terminal sequences encoded by exons 12-15 were present. These data indicate the presence of fibrillin-1 molecular recognition sequences within the amino terminus and the extreme carboxy-terminal sequence downstream of the furin site, and a specific amino- and carboxy-terminal association which could drive overlapping linear accretion of furin-processed fibrillin molecules in the extracellular space. Differences in processing of the two fibrillin isoforms may reflect differential abilities to assemble in the extracellular space.


Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth.
ALR (MLL2) is a member of the human MLL family, which belongs to a larger SET1 family of histone methyltransferases. We found that ALR is present within a stable multiprotein complex containing a cohort of proteins shared with other SET1 family complexes and several unique components, such as PTIP and the jumonji family member UTX. Like other complexes formed by SET1 family members, the ALR complex exhibited strong H3K4 methyltransferase activity, conferred by the ALR SET domain. By generating ALR knockdown cell lines and comparing their expression profiles to that of control cells, we identified a set of genes whose expression is activated by ALR. Some of these genes were identified by chromatin immunoprecipitation as direct ALR targets. The ALR complex was found to associate in an ALR-dependent fashion with promoters and transcription initiation sites of target genes and to induce H3K4 trimethylation. The most characteristic features of the ALR knockdown cells were changes in the dynamics and mode of cell spreading/polarization, reduced migration capacity, impaired anchorage-dependent and -independent growth, and decreased tumorigenicity in mice. Taken together, our results suggest that ALR is a transcriptional activator that induces the transcription of target genes by covalent histone modification. ALR appears to be involved in the regulation of adhesion-related cytoskeletal events, which might affect cell growth and survival.


Symptoms of PTSD Associated With Painful and Nonpainful Vicarious Reactivity Following Amputation.
Although the experience of vicarious sensations when observing another in pain have been described postamputation, the underlying mechanisms are unknown. We investigated whether vicarious sensations are related to posttraumatic stress disorder (PTSD) symptoms and chronic pain. In Study 1, 236 amputees completed questionnaires about phantom limb phenomena and vicarious sensations to both innocuous and painful sensory experiences of others. There was a 10.2% incidence of vicarious sensations, which was significantly more prevalent in amputees reporting PTSD-like experiences, particularly increased arousal and reexperiencing the event that led to amputation (φ = .16). In Study 2, 63 amputees completed the Empathy for Pain Scale and PTSD Checklist-Civilian Version. Cluster analyses revealed 3 groups: 1 group did not experience vicarious pain or PTSD symptoms, and 2 groups were vicarious pain responders, but only 1 had increased PTSD symptoms. Only the latter group showed increased chronic pain severity compared with the nonresponder group (p = .025) with a moderate effect size (r = .35). The findings from both studies implicated an overlap, but also divergence, between PTSD symptoms and vicarious pain reactivity postamputation. Maladaptive mechanisms implicated in severe chronic pain and physical reactivity posttrauma may increase the incidence of vicarious reactivity to the pain of others.


[Analysis on "component-target-pathway" of Paeonia lactiflora in treating cardiac diseases based on data mining].
Based on the literature review and modern application of Paeonia lactiflora in heart diseases, this article would predict the target of drug and disease by intergrative pharmacology platform of traditional Chinese medicine (TCMIP, http://www.tcmip.cn), and then explore the molecular mechanism of P. lactiflora in treatment of heart disease, providing theoretical basis and method for further studies on P. lactiflora. According to the ancient books, P. lactiflora with functions of "removing the vascular obstruction, removing the lumps, relieving pain, diuretic, nutrient qi" and other effects, have been used for many times to treat heart disease. Some prescriptions are also favored by the modern physicians nowadays. With the development of science, the chemical components that play a role in heart disease and the interrelation between these components and the body become the research hotspot. In order to further reveal the pharmacological substance base and molecular mechanism of P. lactiflora for the treatment of such diseases, TCM-IP was used to obtain multiple molecular targets and signaling pathways in treatment of heart disease. ATP1A1, a common target of drug and disease, was related to energy, and HDAC2 mainly regulated cardiomyocyte hypertrophy gene and cardiomyocyte expression. Other main drug targets such as GCK, CHUK and PRKAA2 indirectly regulated heart disease through many pathways; multiple disease-associated signaling pathways interfered with various heart diseases including coronary heart disease, myocardial ischemia and myocardial hypertrophy through influencing energy metabolism, enzyme activity and gene expression. In conclusion, P. lactiflora plays a role in protecting heart function by regulating the gene expression of cardiomyocytes directly. Meanwhile, it can indirectly intervene in other pathways of heart function, and thus participate in the treatment of heart disease. In this paper, the molecular mechanism of P. lactiflora for treatment of heart disease was in computer prediction analysis level, and the specific mechanism of action still needs further experimental verification.


Raw material optimization and stone tool engineering in the Early Stone Age of Olduvai Gorge (Tanzania).
For more than 1.8 million years hominins at Olduvai Gorge were faced with a choice: whether to use lavas, quartzite or chert to produce stone tools. All are available locally and all are suitable for stone tool production. Using controlled cutting tests and fracture mechanics theory we examine raw material selection decisions throughout Olduvai's Early Stone Age. We quantify the force, work and material deformation required by each stone type when cutting, before using these data to compare edge sharpness and durability. Significant differences are identified, confirming performance to depend on raw material choice. When combined with artefact data, we demonstrate that Early Stone Age hominins optimized raw material choices based on functional performance characteristics. Doing so flexibly: choosing raw materials dependent on their sharpness and durability, alongside a tool's loading potential and anticipated use-life. In this way, we demonstrate that early lithic artefacts at Olduvai Gorge were engineered to be functionally optimized cutting tools.


Non-antipsychotic catecholaminergic drugs for antipsychotic-induced tardive dyskinesia.
Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of antipsychotic medication. Several strategies have been examined in the treatment of TD. Currently, however, there is no clear evidence of the effectiveness of these drugs in TD and they have been associated with many side effects. One particular strategy would be to use pharmaceutical agents which are known to influence the catecholaminergic system at various junctures. 1. To determine the effects of any of the following drugs for antipsychotic-induced TD in people with schizophrenia or other chronic mental illnesses.i. Drugs which influence the noradrenergic system.ii. Dopamine receptor agonists.iii. Dopamine receptor antagonists.iv. Dopamine-depletor drugs.v. Drugs that increase the production or release of dopamine.2. To examine whether any improvement occurred with short periods of intervention (less than 6 weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.3. To examine if there was a differential effect for the various compounds.4. To examine whether the use of non-antipsychotic catecholaminergic drugs are most effective in those with more recent onset TD (less than five years). We retrieved 712 references from searching the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information. We selected studies if they were randomised controlled trials focusing on people with schizophrenia or other chronic mental illnesses and antipsychotic-induced tardive dyskinesia. We compared the use of catecholaminergic interventions versus placebo, no intervention, or any other intervention for the treatment of antipsychotic-induced tardive dyskinesia. We independently extracted data from these trials and we estimated risk ratios (RRs) with 95% confidence intervals (CIs). We assumed that people who left the studies early had no improvement. There are 10 included trials (N = 261) published between 1973 and 2010; eight are new from the 2015 and 2017 update searches. Forty-eight studies are excluded. Participants were mostly chronically mentally ill inpatients in their 50s, and studies were primarily of short (2 to 6 weeks) duration. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment and generation of the sequence. Studies were also not clearly blinded and we are unsure if data are incomplete or selectively reported, or if other biases were operating.One small, three-arm trial found that both alpha-methyldopa (N = 20; RR 0.33, 95% CI 0.14 to 0.80; low-quality evidence) and reserpine (N = 20; RR 0.52 95% CI 0.29 to 0.96; low-quality evidence) may lead to a clinically important improvement in tardive dyskinesia symptoms compared with placebo after 2 weeks' treatment, but found no evidence of a difference between alpha-methyldopa and reserpine (N = 20; RR 0.60, 95% CI 0.19 to 1.86; very low quality evidence). Another small trial compared tetrabenazine and haloperidol after 18 weeks' treatment and found no evidence of a difference on clinically important improvement in tardive dyskinesia symptoms (N = 13; RR 0.93, 95% CI 0.45 to 1.95; very low quality evidence). No study reported on adverse events.For remaining outcomes there was no evidence of a difference between any of the interventions: alpha-methyldopa versus placebo for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence), celiprolol versus placebo for leaving the study early (1 RCT; N = 35; RR 5.28, 95% CI 0.27 to 102.58; very low quality evidence) and quality of life (1 RCT; N = 35; RR 0.87, 95% CI 0.68 to 1.12; very low quality evidence), alpha-methyldopa versus reserpine for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; not estimable, no reported events; very low quality evidence), reserpine or carbidopa/levodopa versus placebo for deterioration of tardive dyskinesia symptoms (2 RCTs; N = 37; RR 1.18, 95% CI 0.35 to 3.99; very low quality evidence), oxypertine versus placebo for deterioration of mental state (1 RCT; N = 42; RR 2.20, 95% CI 0.22 to 22.45; very low quality evidence), dopaminergic drugs (amantadine, bromocriptine, tiapride, oxypertine, carbidopa/levodopa) versus placebo for leaving the study early (6 RCTs; N = 163; RR 1.29, 95% CI 0.65 to 2.54; very low quality evidence), and tetrabenazine versus haloperidol for deterioration of tardive dyskinesia symptoms (1 RCT; N = 13; RR 1.17, 95% CI 0.09 to 14.92) and leaving the study early (1 RCT; N = 13; RR 0.23, 95% CI 0.01 to 4.00). Although there has been a large amount of research in this area, many studies were excluded due to inherent problems in the nature of their cross-over designs. Usually data are not reported before the cross-over and the nature of TD and its likely response to treatments make it imprudent to use this data. The review provides little usable information for service users or providers and more well-designed and well-reported studies are indicated.


Dissociable control of impulsivity in rats by dopamine d2/3 receptors in the core and shell subregions of the nucleus accumbens.
Previous research has identified the nucleus accumbens (NAcb) as an important brain region underlying inter-individual variation in impulsive behavior. Such variation has been linked to decreased dopamine (DA) D2/3 receptor availability in the ventral striatum of rats exhibiting spontaneously high levels of impulsivity on a 5-choice serial reaction time (5-CSRT) test of sustained visual attention. This study investigated the involvement of DA D2/3 receptors in the NAcb core (NAcbC) and the NAcb shell (NAcbS) in impulsivity. We investigated the effects of a DA D2/3 receptor antagonist (nafadotride) and a DA D2/3 partial agonist (aripiprazole) infused directly into either the NAcbC or NAcbS of rats selected for high (HI) and low (LI) impulsivity on the 5-CSRT task. Nafadotride increased significantly the level of impulsivity when infused into the NAcbS, but decreased impulsivity when infused into the NAcbC of HI rats. By contrast, intra-NAcb microinfusions of aripiprazole did not affect impulsivity. Systemic administration of nafadotride had no effect on impulsive behavior but increased the number of omissions and correct response latencies, whereas systemic injections of aripiprazole decreased impulsive and perseverative behavior, and increased the number of omissions and correct response latencies. These findings indicate an opponent modulation of impulsive behavior by DA D2/3 receptors in the NAcbS and NAcbC. Such divergent roles may have relevance for the etiology and treatment of clinical disorders of behavioral control, including attention-deficit hyperactivity disorder and drug addiction.


Association of Prenatal Exposure to Population-Wide Folic Acid Fortification With Altered Cerebral Cortex Maturation in Youths.
Presently, 81 countries mandate the fortification of grain products with folic acid to lessen the risk of neural tube defects in the developing fetus. Epidemiologic data on severe mental illness suggest potentially broader effects of prenatal folate exposure on postnatal brain development, but this link remains unsubstantiated by biological evidence. To evaluate associations among fetal folic acid exposure, cortical maturation, and psychiatric risk in youths. A retrospective, observational clinical cohort study was conducted at Massachusetts General Hospital (MGH) among 292 youths 8 to 18 years of age born between January 1993 and December 2001 (inclusive of folic acid fortification rollout ±3.5 years) with normative results of clinical magnetic resonance imaging, divided into 3 age-matched groups based on birthdate and related level of prenatal folic acid fortification exposure (none, partial, or full). Magnetic resonance imaging was performed between January 2005 and March 2015. Two independent, observational, community-based cohorts (Philadelphia Neurodevelopmental Cohort [PNC] and National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development [NIH]) comprising 1078 youths 8 to 18 years of age born throughout (PNC, 1992-2003) or before (NIH, 1983-1995) the rollout of folic acid fortification were studied for replication, clinical extension, and specificity. Statistical analysis was conducted from 2015 to 2018. United States-mandated grain product fortification with folic acid, introduced in late 1996 and fully in effect by mid-1997. Differences in cortical thickness among nonexposed, partially exposed, and fully exposed youths (MGH) and underlying associations between age and cortical thickness (all cohorts). Analysis of the PNC cohort also examined the association of age-cortical thickness slopes with the odds of psychotic symptoms. The MGH cohort (139 girls and 153 boys; mean [SD] age, 13.3 [2.3] years) demonstrated exposure-associated cortical thickness increases in bilateral frontal and temporal regions (9.9% to 11.6%; corrected P < .001 to P = .03) and emergence of quadratic (delayed) age-associated thinning in temporal and parietal regions (β = -11.1 to -13.9; corrected P = .002). The contemporaneous PNC cohort (417 girls and 444 boys; mean [SD] age, 13.5 [2.7] years) also exhibited exposure-associated delays of cortical thinning (β = -1.59 to -1.73; corrected P < .001 to P = .02), located in similar regions and with similar durations of delay as in the MGH cohort. Flatter thinning profiles in frontal, temporal, and parietal regions were associated with lower odds of psychosis spectrum symptoms in the PNC cohort (odds ratio, 0.37-0.59; corrected P < .05). All identified regions displayed earlier thinning in the nonexposed NIH cohort (118 girls and 99 boys; mean [SD] age, 13.3 [2.6] years). The results of this study suggest an association between gestational exposure to fortification of grain products with folic acid and altered cortical development and, in turn, with reduction in the risk of psychosis in youths.


Social networking and Internet use among pelvic floor patients: a multicenter survey.
Internet resources are becoming increasingly important for patients seeking medical knowledge. It is imperative to understand patient use and preferences for using the Internet and social networking websites to optimize patient education. The purpose of this study was to evaluate social networking and Internet use among women with pelvic floor complaints to seek information for their conditions as well as describe the likelihood, preferences, and predictors of website usage. This was a cross-sectional, multicenter study of women presenting to clinical practices of 10 female pelvic medicine and reconstructive surgery fellowship programs across the United States, affiliated with the Fellows' Pelvic Research Network. New female patients presenting with pelvic floor complaints, including urinary incontinence, pelvic organ prolapse, and fecal incontinence were eligible. Participants completed a 24 item questionnaire designed by the authors to assess demographic information, general Internet use, preferences regarding social networking websites, referral patterns, and resources utilized to learn about their pelvic floor complaints. Internet use was quantified as high (≥4 times/wk), moderate (2-3 times/wk), or minimal (≤1 time/wk). Means were used for normally distributed data and medians for data not meeting this assumption. Fisher's exact and χ2 tests were used to evaluate the associations between variables and Internet use. A total of 282 surveys were analyzed. The majority of participants, 83.3%, were white. The mean age was 55.8 years old. Referrals to urogynecology practices were most frequently from obstetrician/gynecologists (39.9%) and primary care providers (27.8%). Subjects were well distributed geographically, with the largest representation from the South (38.0%). Almost one third (29.9%) were most bothered by prolapse complaints, 22.0% by urgency urinary incontinence, 20.9% by stress urinary incontinence, 14.9% by urgency/frequency symptoms, and 4.1% by fecal incontinence. The majority, 75.0%, described high Internet use, whereas 8.5% moderately and 4.8% minimally used the Internet. Women most often used the Internet for personal motivations including medical research (76.4%), and 42.6% reported Google to be their primary search engine. Despite this, only 4.9% primarily used the Internet to learn about their pelvic floor condition, more commonly consulting an obstetrician-gynecologist for this information (39.4%). The majority (74.1%) held a social networking account, and 45.9% visited these daily. Nearly half, 41.7%, expressed the desire to use social networking websites to learn about their condition. Women <65 years old were significantly more likely to have high Internet use (83.4% vs 68.8%, P = .018) and to desire using social networking websites to learn about their pelvic floor complaint (P = .008). The presenting complaint was not associated with Internet use (P = .905) or the desire to use social networking websites to learn about pelvic floor disorders (P = .201). Women presenting to urogynecology practices have high Internet use and a desire to learn about their conditions via social networking websites. Despite this, obstetrician-gynecologists remain a common resource for information. Nonetheless, urogynecology practices and national organizations would likely benefit from increasing their Internet resources for patient education in pelvic floor disorders, though patients should be made aware of available resources.


Restriction fragment length polymorphism associated with the pro alpha 2(I) gene of human type I procollagen. Application to a family with an autosomal dominant form of osteogenesis imperfecta.
One cloned complementary DNA and one genomic subclone were used to detect restriction fragment length polymorphism associated with the pro alpha 2(I) gene for human type I procollagen. The restriction fragments obtained from examination of 30-122 chromosomes confirmed previous indications that the pro alpha 2(I) gene is found in a single copy in the human haploid genome. One highly polymorphic site was detected with EcoRI in the 5'-half of the gene. The restriction site polymorphism at the site had an allelic frequency of 0.38, and it generated two fragments of 10.5 and 3.5 kilobase in homozygous individuals. The restriction fragment length polymorphism generated at the EcoRI site was used to study affected and non-affected individuals in four generations of a family with an autosomal dominant form of osteogenesis imperfecta. The data demonstrated a linkage of the phenotype to a pro alpha 2(I) allele with a lod score of 2.41 at a recombination fraction (theta) of 0. The data therefore provided presumptive evidence that osteogenesis imperfecta in this family is caused by a mutation in the pro alpha 2(I) gene or some contiguous region of the genome. The relatively high frequency of polymorphism at the EcoRI site makes it useful for studying a broad range of genetic disorders in which mutations in type I procollagen are suspected. In addition, the polymorphic site should provide useful markers for linkage studies with other loci located on human chromosome 7.


Early warning signals and the prosecutor's fallacy.
Early warning signals have been proposed to forecast the possibility of a critical transition, such as the eutrophication of a lake, the collapse of a coral reef or the end of a glacial period. Because such transitions often unfold on temporal and spatial scales that can be difficult to approach by experimental manipulation, research has often relied on historical observations as a source of natural experiments. Here, we examine a critical difference between selecting systems for study based on the fact that we have observed a critical transition and those systems for which we wish to forecast the approach of a transition. This difference arises by conditionally selecting systems known to experience a transition of some sort and failing to account for the bias this introduces--a statistical error often known as the prosecutor's fallacy. By analysing simulated systems that have experienced transitions purely by chance, we reveal an elevated rate of false-positives in common warning signal statistics. We further demonstrate a model-based approach that is less subject to this bias than those more commonly used summary statistics. We note that experimental studies with replicates avoid this pitfall entirely.


Differences in neighborhood social cohesion and aerobic physical activity by Latino subgroup.
Previous research has examined the role of neighborhood social cohesion in physical activity outcomes; however, less is known about this relationship across Latino subgroups. The purpose of our study was to examine the association between neighborhood social cohesion and aerobic leisure-time physical activity (LTPA) among Latino adults and to determine whether these associations differ by Latino subgroup. We used cross-sectional 2013-2014 National Health Interview Survey (NHIS) data on Latinos originating from 5 countries/regions (i.e., Latinos of Puerto Rican, Mexican/Mexican-American, Cuban/Cuban-American, Dominican and Central or South American origin) aged ≥18 years (n=11,126). Multivariable logistic regression models were used to estimate associations between self-reported neighborhood social cohesion and meeting aerobic LTPA guidelines. Models were adjusted for age, sex, education, and acculturation. We also investigated whether associations varied by Latino subgroup. In adjusted models for all Latino adults, compared with those reporting low social cohesion, individuals who reported high social cohesion (Odds Ratio [OR]: 1.33; 95% Confidence Interval [CI]: 1.17-1.52) were significantly more likely to meet the aerobic physical activity guideline. When stratified by Latino subgroups, among Mexican/Mexicans-Americans (OR: 1.39; 95% CI: 1.16, 1.66) and Cuban/Cuban Americans (OR: 1.73; 95% CI: 1.00, 2.97) high social cohesion was associated with meeting the aerobic activity guideline. Among Dominicans, those who reported medium social cohesion (OR: 0.52, 95% CI: 0.29, 0.93) were less likely to meet the aerobic activity guideline. When examining aerobic physical activity outcomes in the Latino population, the role of neighborhood social cohesion and the variability among Latino subgroups should be considered.


Drastic therapy for listerial brain abscess involving combined hyperbaric oxygen therapy and antimicrobial agents.
Listeria monocytogenes (L. monocytogenes) is a rare causative pathogen of brain abscess that is often found in immunocompromised patients. Although patients with supratentorial listerial abscesses showed a longer survival with surgical drainage, the standard therapy for patients with subtentorial lesions has not been established. We report herein a patient with supra- and subtentorial brain abscesses caused by L. monocytogenes infection. These abscesses did not respond to antibiotics, and his symptoms gradually worsened. Drainage was not indicated for subtentorial lesions, and the patient was additionally treated with hyperbaric oxygen therapy, which dramatically reduced the volume of abscesses and improved the symptoms. This is the first report of drastic therapy for a patient with listerial brain abscesses involving combined antibiotics and hyperbaric oxygen therapy. The findings suggest that hyperbaric oxygen therapy is a good option for treating patients with deep-seated listerial abscesses and for who surgical drainage is not indicated.


Feasibility of Using a Wearable Biosensor Device in Patients at Risk for Alzheimer's Disease Dementia.
Alzheimer's disease (AD) is the most common and most costly chronic neurodegenerative disease globally. AD develops over an extended period prior to cognitive symptoms, leaving a "window of opportunity" for targeted risk-reduction interventions. Further, this pre-dementia phase includes early physiological changes in sleep and autonomic regulation, for which wearable biosensor devices may offer a convenient and cost-effective method to assess AD-risk. Patients with a family history of AD and no or minimal cognitive complaints were recruited from the Alzheimer's Prevention Clinic at Weill Cornell Medicine and New York-Presbyterian. Of the 40 consecutive patients screened, 34 (85%) agreed to wear a wearable biosensor device (WHOOP). One subject (2.5%) lost the device prior to data collection. Of the remaining subjects, 24 were classified as normal cognition and were asymptomatic, 6 were classified as subjective cognitive decline, and 3 were amyloid-positive (one with pre-clinical AD, one with pre-clinical Lewy-Body Dementia, and one with mild cognitive impairment due to AD). Sleep-cycle, autonomic (heart rate variability [HRV]) and activity measures were collected via WHOOP. Blood biomarkers and neuropsychological testing sensitive to cognitive changes in pre-clinical AD were obtained. Participants completed surveys assessing their sleep-patterns, exercise habits, and attitudes towards WHOOP. The goal of this prospective observational study was to determine the feasibility of using a wrist-worn biosensor device in patients at-risk for AD dementia. Unsupervised machine learning was performed to first separate participants into distinct phenotypic groups using the multivariate biometric data. Additional statistical analyses were conducted to examine correlations between individual biometric measures and cognitive performance. 27 (81.8%) participants completed the follow-up surveys. Twenty-four participants (88.9%) were satisfied with WHOOP after six months, and twenty-three (85.2%) wanted to continue wearing WHOOP. K-means clustering separated participants into two groups. Group 1 was older, had lower HRV, and spent more time in slow-wave sleep (SWS) than Group 2. Group 1 performed better on two cognitive tests assessing executive function: Flanker Inhibitory Attention/Control (FIAC) (p=.031), and Dimensional Change Card Sort (DCCS) (p=.061). In Group 1, DCCS was correlated with SWS (ρ=.68, p=0.024) and HRV (ρ=.6, p=0.019). In Group 2, DCCS was correlated with HRV (ρ=.55, p=0.018). There were no significant differences in blood biomarkers between the two groups. Wearable biosensor devices may be a feasible tool to assess AD-related physiological changes. Longitudinal collection of sleep and HRV data may potentially be a non-invasive method for monitoring cognitive changes related to pre-clinical AD. Further study is warranted in larger populations.


The Effects of Training on Knowledge and Beliefs About Breast Cancer and Early Diagnosis Methods Among Women.
Breast cancer (BC) is the most common female malignancy in the world and Turkey. Its prevalence and mortality are surprisingly increasing at a rapid rate. The objective of this study was to determine the effectiveness of training sessions on women's knowledge of relevant risk factors of BC and screening methods, screening behaviors and health beliefs among of healthy women in Turkey. In this study, in order to establish the efficiency of BC training, a semi-empirical single group pre-test & post-test research model was used. The data were collected by using a self-administered questionnaire and by using the Turkish version of Champion's health belief model scale (CHBMS). The pre-test was performed before the training and after one week of the training, post-test was performed with a questionnaire having the same content. In total, 244 women participated in the study. The average age of the women was 39.44 (SD=1.06) years. The mean total knowledge score increased significantly (p<.001) from 9.05 in the pre-test to 16.53 in the post-test. The results showed that both mean knowledge scores and CHBMS subscales scores of the women were increased significantly (p<.001) from the pre-test to the post-test. In multiple linear regression analysis, BC screening knowledge of women with susceptibility, benefit, self-efficacy and health motivation subscales of CHBMS, breast self-examination (BSE) practice and self-efficacy were also significant in the post-test; in the pre- and post-tests, a significant relationship among the level of education of women, susceptibility and seriousness was found (p<.001). The study showed that the training program had profound effects on BC knowledge, screening behaviors and health beliefs of women.


A pilot investigation using global positioning systems into the outdoor activity of people with severe traumatic brain injury.
Little is known about the post-discharge outdoor activities of people who have incurred severe traumatic brain injury (TBI). This study used a body-worn global positioning system (GPS) device to determine the outdoor activity per day performed by this population. Additionally, this study examined the association that mobility, time since injury and injury severity had with levels of outdoor physical activity. Seventeen people with TBI and 15 control subjects wore a GPS device for between 3-7 days to monitor their outdoor activity. Based on the individual's location and speed of movement the outdoor physical activity in minutes per day was derived. Assessments of duration of outdoor activity between groups, and the relationship that duration of outdoor activity had with results on the high-level mobility assessment tool, length of post-traumatic amnesia, and time since injury were performed. No significant (p = 0.153, effect size = 0.26) difference in time spent in outdoor physical activity was observed between the TBI (median[IQR] = 19[3-43]mins) and control (median[IQR] = 50[18-65]mins) group. Interestingly, 35% of TBI subjects performed <10 mins of outdoor activity per day compared to 13% of the control group. The TBI group also recorded three of the four highest values for outdoor physical activity. Higher levels of mobility were associated with more outdoor activity (Spearman's rho = 0.443, p = 0.038). No other significant associations were observed. While preliminary, our results indicate that a sub-group of people with TBI exists who restrict their outdoor activities. GPS has potential as an activity tracking tool, with implications for rehabilitation and exercise prescription.


The effects of aquatic, isometric strength-stretching and aerobic exercise on physical and psychological parameters of female patients with fibromyalgia syndrome.
[Purpose] There are various treatment modalities for fibromyalgia syndrome (FMS), which is characterized by widespread pain and fatigue. The aim of this study was to investigate the effects of aquatic, aerobic and isometric strength-stretching exercises on the physical and psychological parameters of patients with FMS. [Subjects and Methods] Seventy five female patients with FMS were randomly selected and divided into three groups. Patients (18-50 years) were treated for 3 months using one of three methods: a home-based isometric strength and stretching exercise program (ISSEP), a gym-based aerobic exercise program (AEP), and a pool-based aquatic aerobic exercise program (AAEP). Items evaluated were: the number of tender points, Visual Analog Scale (VAS), Fibromyalgia Impact Questionnaire (FIQ), the Six-Minute Walk Test (6MWT), SF-36 physical and mental health scores, and the Beck Depression Inventory (BDI). [Results] The results revealed that AAEP was the most effective treatment of the three. All of the groups showed significant improvements in all variables between pre-and post-test, except the mean values of VAS and BDI in ISSEP. [Conclusion] The results suggest that aquatic aerobic exercise program is more effective than AEP and ISSEP in the treatment of FMS.


Strength-training behavior and perceived environment among Japanese older adults.
The authors examined the relationship between strength-training behavior and perceived environment in older Japanese adults. An Internet-based survey was conducted of 293 adults age 68.2 ± 2.8 yr. The dependent variable was regular strength-training behavior. The IPAQ environment module, access to facilities for strength training, and home equipment for strength training were environmental factors. Logistic-regression analysis was employed. After demographic variables (gender, age, educational background, household income, body-mass index, self-rated health status, smoking habit, and residential area) were adjusted for, home equipment for strength training (OR = 2.14, 95% CI = 1.50-3.06), access to facilities for strength training (OR = 2.53, 95% CI = 1.32-4.85), and observing active people (OR = 2.20, 95% CI = 1.06-4.58) were positively correlated with regular strength-training behavior. In conclusion, environmental factors associated with strength-training behavior were access to facilities for strength training, having home equipment for strength training, and observing active people.


A comparison of population versus individual based cardiovascular disease prevention programs in Västerbotten, Sweden.
The purpose of this paper is to determine if differences in health outcomes of two cardiovascular disease prevention programs can be attributed to the inclusion of population based efforts in one of the programs. Propensity score matching has been used to eliminate possible selection bias. The results indicate that the intervention including population-based measures was not more effective than the intervention directed toward the individual.


Rhinosinusitis and comorbidities.
A variety of systemic conditions impact the incidence, severity, prognosis, and treatment approach in patients with chronic rhinosinusitis (CRS). The controversy surrounding the impact of allergic rhinitis on CRS continues, but it is reasonable to consider and treat allergic sources of inflammation in any patient with CRS. CRS is more severe in patients with aspirin sensitivity but improves--at least temporarily--to the same degree as in non-aspirin-sensitive patients, given appropriate therapy. Polypoid rhinosinusitis in cystic fibrosis patients is characterized by compromised mucociliary clearance and infection with staphylococcal and pseudomonal organisms. Affected individuals require frequent antibiotic treatment, saline lavage, and repeated surgeries. Rhinosinusitis is among the most common infectious complications of humoral immunodeficiency, which is not uncommon in patients with refractory CRS. The treatment approach in immunodeficiency includes aggressive antibiotic treatment and intravenous immunoglobulin. Specific diagnosis of comorbid systemic conditions with CRS will facilitate appropriate management.


Text Detection and Recognition in Imagery: A Survey.
This paper analyzes, compares, and contrasts technical challenges, methods, and the performance of text detection and recognition research in color imagery. It summarizes the fundamental problems and enumerates factors that should be considered when addressing these problems. Existing techniques are categorized as either stepwise or integrated and sub-problems are highlighted including text localization, verification, segmentation and recognition. Special issues associated with the enhancement of degraded text and the processing of video text, multi-oriented, perspectively distorted and multilingual text are also addressed. The categories and sub-categories of text are illustrated, benchmark datasets are enumerated, and the performance of the most representative approaches is compared. This review provides a fundamental comparison and analysis of the remaining problems in the field.


Observation of the diphoton decay of the Higgs boson and measurement of its properties.
Observation of the diphoton decay mode of the recently discovered Higgs boson and measurement of some of its properties are reported. The analysis uses the entire dataset collected by the CMS experiment in proton-proton collisions during the 2011 and 2012 LHC running periods. The data samples correspond to integrated luminosities of 5.1[Formula: see text]at [Formula: see text] and 19.7[Formula: see text]at 8[Formula: see text] . A clear signal is observed in the diphoton channel at a mass close to 125[Formula: see text] with a local significance of [Formula: see text], where a significance of [Formula: see text] is expected for the standard model Higgs boson. The mass is measured to be [Formula: see text] , and the best-fit signal strength relative to the standard model prediction is [Formula: see text][Formula: see text][Formula: see text]. Additional measurements include the signal strength modifiers associated with different production mechanisms, and hypothesis tests between spin-0 and spin-2 models.


The Efficacy of Short-term Gated Audiovisual Speech Training for Improving Auditory Sentence Identification in Noise in Elderly Hearing Aid Users.
This study aimed to examine the efficacy and maintenance of short-term (one-session) gated audiovisual speech training for improving auditory sentence identification in noise in experienced elderly hearing-aid users. Twenty-five hearing aid users (16 men and 9 women), with an average age of 70.8 years, were randomly divided into an experimental (audiovisual training, n = 14) and a control (auditory training, n = 11) group. Participants underwent gated speech identification tasks comprising Swedish consonants and words presented at 65 dB sound pressure level with a 0 dB signal-to-noise ratio (steady-state broadband noise), in audiovisual or auditory-only training conditions. The Hearing-in-Noise Test was employed to measure participants' auditory sentence identification in noise before the training (pre-test), promptly after training (post-test), and 1 month after training (one-month follow-up). The results showed that audiovisual training improved auditory sentence identification in noise promptly after the training (post-test vs. pre-test scores); furthermore, this improvement was maintained 1 month after the training (one-month follow-up vs. pre-test scores). Such improvement was not observed in the control group, neither promptly after the training nor at the one-month follow-up. However, no significant between-groups difference nor an interaction between groups and session was observed. Audiovisual training may be considered in aural rehabilitation of hearing aid users to improve listening capabilities in noisy conditions. However, the lack of a significant between-groups effect (audiovisual vs. auditory) or an interaction between group and session calls for further research.


Carbon Dioxide Laser Plus Topical 5% Luliconazole: A Better Combination Therapeutic Modality for Onychomycosis.
Onychomycosis has always been a therapeutic challenge because of longer treatment duration, potential adverse effects of oral antifungals, and limited efficacy of topical agents. During the past few years, the emergence of laser therapy has been the topic of discussion as a newer, safe, minimally invasive modality of treatment. The aim of this study was to evaluate the role of fractional CO2 laser and topical luliconazole 5% lotion in the treatment of onychomycosis, as a combined treatment and as independent modalities. This was a prospective, randomized, triple-limb comparative observational study in which 106 patients with KOH and culture-proven onychomycosis were randomly assigned to three groups. Group A received fractional CO2 laser (10,600nm) triweekly for four sessions (0, 3, 9, and 12 weeks) plus topical luliconazole 5.0% lotion applied twice daily on the affected nail plates and nail folds for 12 weeks. Group B received only fractional CO2 with the same frequency of sessions and laser parameters as in group A. Group C received only topical luliconazole 5.0% solution twice daily for 12 weeks. Treatment outcome was evaluated using onychomycosis severity index (OSI) score, mycological parameters, and level of satisfaction of patients. The degree of clinical improvement, mycological cure, and patient's satisfaction was significantly better in the combined group than individual modalities. There were no severe adverse effects that warranted the discontinuation of the treatment in any of these patients. Fractional CO2 laser combined with topical luliconazole 5% lotion is a safe and effective treatment for onychomycosis especially in those who have contraindications to oral antifungals.


Tuberculosis Prevention in the Private Sector: Using Claims-Based Methods to Identify and Evaluate Latent Tuberculosis Infection Treatment With Isoniazid Among the Commercially Insured.
Targeted identification and treatment of people with latent tuberculosis infection (LTBI) are key components of the US tuberculosis elimination strategy. Because of recent policy changes, some LTBI treatment may shift from public health departments to the private sector. To (1) develop methodology to estimate initiation and completion of treatment with isoniazid for LTBI using claims data, and (2) estimate treatment completion rates for isoniazid regimens from commercial insurance claims. Medical and pharmacy claims data representing insurance-paid services rendered and prescriptions filled between January 2011 and March 2015 were analyzed. Four million commercially insured individuals 0 to 64 years of age. Six-month and 9-month treatment completion rates for isoniazid LTBI regimens. There was an annual isoniazid LTBI treatment initiation rate of 12.5/100 000 insured persons. Of 1074 unique courses of treatment with isoniazid for which treatment completion could be assessed, almost half (46.3%; confidence interval, 43.3-49.3) completed 6 or more months of therapy. Of those, approximately half (48.9%; confidence interval, 44.5-53.3) completed 9 months or more. Claims data can be used to identify and evaluate LTBI treatment with isoniazid occurring in the commercial sector. Completion rates were in the range of those found in public health settings. These findings suggest that the commercial sector may be a valuable adjunct to more traditional venues for tuberculosis prevention. In addition, these newly developed claims-based methods offer a means to gain important insights and open new avenues to monitor, evaluate, and coordinate tuberculosis prevention.


Sialic acid recognition by Vibrio cholerae neuraminidase.
Vibrio cholerae neuraminidase (VCNA) plays a significant role in the pathogenesis of cholera by removing sialic acid from higher order gangliosides to unmask GM1, the receptor for cholera toxin. We previously showed that the structure of VCNA is composed of a central beta-propeller catalytic domain flanked by two lectin-like domains; however the nature of the carbohydrates recognized by these lectin domains has remained unknown. We present here structures of the enzyme in complex with two substrates, alpha-2,3-sialyllactose and alpha-2,6-sialyllactose. Both substrate complexes reveal the alpha-anomer of N-acetylneuraminic acid (Neu5Ac) bound to the N-terminal lectin domain, thereby revealing the role of this domain. The large number of interactions suggest a relatively high binding affinity for sialic acid, which was confirmed by calorimetry, which gave a Kd approximately 30 microm. Saturation transfer difference NMR using a non-hydrolyzable substrate, Neu5,9Ac2-2-S-(alpha-2,6)-GlcNAcbeta1Me, was also used to map the ligand interactions at the VCNA lectin binding site. It is well known that VCNA can hydrolyze both alpha-2,3- and alpha-2,6-linked sialic acid substrates. In this study using alpha-2,3-sialyllactose co-crystallized with VCNA it was revealed that the inhibitor 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en) was bound at the catalytic site. This observation supports the notion that VCNA can produce its own inhibitor and has been further confirmed by 1H NMR analysis. The discovery of the sialic acid binding site in the N-lectin-like domain suggests that this might help target VCNA to sialic acid-rich environments, thereby enhancing the catalytic efficiency of the enzyme.


Search for resonant diboson production in the [Formula: see text] final state in [Formula: see text] collisions at [Formula: see text] TeV with the ATLAS detector.
This paper reports on a search for narrow resonances in diboson production in the [Formula: see text] final state using [Formula: see text] collision data corresponding to an integrated luminosity of [Formula: see text] fb[Formula: see text] collected at [Formula: see text] TeV with the ATLAS detector at the Large Hadron Collider. No significant excess of data events over the Standard Model expectation is observed. Upper limits at the 95 % confidence level are set on the production cross section times branching ratio for Kaluza-Klein gravitons predicted by the Randall-Sundrum model and for Extended Gauge Model [Formula: see text] bosons. These results lead to the exclusion of mass values below 740 and 1590 GeV for the graviton and [Formula: see text] boson respectively.


Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities.
Although central leptin signaling appears to play a major role in the regulation of food intake and energy metabolism, the physiological role of peripheral leptin signaling and its relative contribution to whole-body energy metabolism remain unclear. To address this question, we created a mouse model (Cre-Tam mice) with an intact leptin receptor in the brain but a near-complete deletion of the signaling domain of leptin receptor in liver, adipose tissue, and small intestine using a tamoxifen (Tam)-inducible Cre-LoxP system. Cre-Tam mice developed marked hyperleptinemia (approximately 4-fold; P < 0.01) associated with 2.3-fold increase (P < 0.05) in posttranscriptional production of leptin. Whereas this is consistent with the disruption of a negative feedback regulation of leptin production in adipose tissue, there were no discernable changes in energy balance, thermoregulation, and insulin sensitivity. Hypothalamic levels of phosphorylated signal transducer and activator of transcription 3, neuropeptide expression, and food intake were not changed despite hyperleptinemia. The percentage of plasma-bound leptin was markedly increased (90.1-96 vs. 41.8-74.7%; P < 0.05), but plasma-free leptin concentrations remained unaltered in Cre-Tam mice. We conclude from these results that 1) the relative contribution to whole-body energy metabolism from peripheral leptin signaling is insignificant in vivo, 2) leptin signaling in adipocyte constitutes a distinct short-loop negative feedback regulation of leptin production that is independent of tissue metabolic status, and 3) perturbation of peripheral leptin signaling alone, although increasing leptin production, may not be sufficient to alter the effective plasma levels of leptin because of the counter-regulatory increase in the level of leptin binding protein(s).


Soft tissue sarcoma, version 2.2014.
These NCCN Guidelines Insights highlight the important updates to the NCCN Guidelines for Soft Tissue Sarcoma (STS) specific to the role of radiation therapy in the management of patients with retroperitoneal/intra-abdominal STS. The guidelines have also included recommendations for genetic testing and counseling for patients with a clinical and/or family history of genetic cancer syndromes associated with a predisposition for the development of STS.


Effect of Depth of Sedation in Older Patients Undergoing Hip Fracture Repair on Postoperative Delirium: The STRIDE Randomized Clinical Trial.
Postoperative delirium is the most common complication following major surgery in older patients. Intraoperative sedation levels are a possible modifiable risk factor for postoperative delirium. To determine whether limiting sedation levels during spinal anesthesia reduces incident delirium overall. This double-blind randomized clinical trial (A Strategy to Reduce the Incidence of Postoperative Delirum in Elderly Patients [STRIDE]) was conducted from November 18, 2011, to May 19, 2016, at a single academic medical center and included a consecutive sample of older patients (≥65 years) who were undergoing nonelective hip fracture repair with spinal anesthesia and propofol sedation. Patients were excluded for preoperative delirium or severe dementia. Of 538 hip fractures screened, 225 patients (41.8%) were eligible, 10 (1.9%) declined participation, 15 (2.8%) became ineligible between the time of consent and surgery, and 200 (37.2%) were randomized. The follow-up included postoperative days 1 to 5 or until hospital discharge. Heavier (modified observer's assessment of sedation score of 0-2) or lighter (observer's assessment of sedation score of 3-5) propofol sedation levels intraoperatively. Delirium on postoperative days 1 to 5 or until hospital discharge determined via consensus panel using Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria. The incidence of delirium was compared between intervention groups with and without stratification by the Charlson comorbidity index (CCI). Of 200 participants, the mean (SD) age was 82 (8) years, 146 (73%) were women, 194 (97%) were white, and the mean (SD) CCI was 1.5 (1.8). One hundred participants each were randomized to receive lighter sedation levels or heavier sedation levels. A good separation of intraoperative sedation levels was confirmed by multiple indices. The overall incident delirium risk was 36.5% (n = 73) and 39% (n = 39) vs 34% (n = 34) in heavier and lighter sedation groups, respectively (P = .46). Intention-to-treat analyses indicated no statistically significant difference between groups in the risk of incident delirium (log-rank test χ2, 0.46; P = .46). However, in a prespecified subgroup analysis, when stratified by CCI, sedation levels did effect the delirium risk (P for interaction = .04); in low comorbid states (CCI = 0), heavier vs lighter sedation levels doubled the risk of delirium (hazard ratio, 2.3; 95% CI, 1.1- 4.9). The level of sedation did not affect delirium risk with a CCI of more than 0. In the primary analysis, limiting the level of sedation provided no significant benefit in reducing incident delirium. However, in a prespecified subgroup analysis, lighter sedation levels benefitted reducing postoperative delirium for persons with a CCI of 0. clinicaltrials.gov Identifier: NCT00590707.


Androgen response element of the glycine N-methyltransferase gene is located in the coding region of its first exon.
Androgen plays an important role in the pathogenesis of PCa (prostate cancer). Previously, we identified GNMT (glycine N-methyltransferase) as a tumour susceptibility gene and characterized its promoter region. Besides, its enzymatic product-sarcosine has been recognized as a marker for prognosis of PCa. The goals of this study were to determine whether GNMT is regulated by androgen and to map its AREs (androgen response elements). Real-time PCR analyses showed that R1881, a synthetic AR (androgen receptor) agonist induced GNMT expression in AR-positive LNCaP cells, but not in AR-negative DU145 cells. In silico prediction showed that there are four putative AREs in GNMT-ARE1, ARE2 and ARE3 are located in the intron 1 and ARE4 is in the intron 2. Consensus ARE motif deduced from published AREs was used to identify the fifth ARE-ARE5 in the coding region of exon 1. Luciferase reporter assay found that only ARE5 mediated the transcriptional activation of R1881. ARE3 overlaps with a YY1 [Yin and Yang 1 (motif (CaCCATGTT, +1118/+1126)] that was further confirmed by antibody supershift and ChIP (chromatin immunoprecipitation) assays. EMSA (electrophoretic mobility shift assay) and ChIP assay confirmed that AR interacts with ARE5 in vitro and in vivo. In summary, GNMT is an AR-targeted gene with its functional ARE located at +19/+33 of the first exon. These results are valuable for the study of the influence of androgen on the gene expression of GNMT especially in the pathogenesis of cancer.


Treatment of central and sensorineural tinnitus with orally administered Melatonin and Sulodexide: personal experience from a randomized controlled study.
Since very little is understood about the exact aetiology of tinnitus, this has made treatment of the condition difficult. Even though approximately 10-15% of the general population suffer from tinnitus, only 2% consider it serious enough to warrant any treatment. The main problem arising from tinnitus is the disturbance it causes not only in day to day life but also in sleep, leading to fatigue and general discomfort. The present study focused on the effect of Melatonin in conjunction with Sulodexide as a treatment method for tinnitus. Overall, 102 patients suffering from tinnitus were evaluated in a prospective randomised controlled study conducted in a tertiary care ENT department. After randomisation, 34 patients were treated with Melatonin and Sulodexide, another 34 were treated with Melatonin alone, while the remaining 34 (control group) were managed without treatment in order to evaluate spontaneous variations in the quality of tinnitus. Patients were assessed prospectively with the Tinnitus Handicap Inventory and Acufenometry, both pre- and post-treatment. Among the patients studied, better results with both Tinnitus Handicap Inventory and Acufenometry were found in the group who received Melatonin and Sulodexide compared to those receiving Melatonin alone. No improvement was observed in the control group. In conclusion, Melatonin in combination with Sulodexide is, in our opinion, a viable treatment option for patients suffering from central or sensorineural tinnitus.


Efficacy and tolerability of ziprasidone versus risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder: an 8-week, double-blind, multicenter trial.
More head-to-head comparisons of antipsychotics are needed to discern the relative efficacy and safety profiles of these compounds. Thus, we compared ziprasidone and risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder. Patients with DSM-III-R acute exacerbation of schizophrenia or schizoaffective disorder were randomly assigned to double-blind ziprasidone 40 to 80 mg b.i.d. (N = 149) or risperidone 3 to 5 mg b.i.d (N = 147) for 8 weeks. Primary efficacy measures included Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness scale (CGI-S) score; secondary measures included scores on the PANSS negative sub-scale, CGI-Improvement scale (CGI-I), and PANSS-derived Brief Psychiatric Rating Scale (BPRSd) total and core items. Safety assessments included movement disorder evaluations, laboratory tests, electrocardiography, vital signs, and body weight. Efficacy analyses employed a prospectively defined Evaluable Patients cohort. Treatment equivalence was conferred if the lower limit of the 95% confidence interval of the ziprasidone/risperidone ratio of least-squares mean change from baseline was > 0.60. Data were gathered from August 1995 to January 1997. Equivalence was demonstrated in PANSS total scores, CGI-S scores, PANSS negative subscale scores, BPRSd total and core item scores, and PANSS total and CGI-I responder rates. Both agents were well tolerated. Risperidone exhibited a significantly higher Movement Disorder Burden (MDB) score (p < .05) and higher incidences of prolactin elevation and clinically relevant weight gain. However, compared with current recommendations, study dosing may have been high for some risperidone-treated patients (mean dose = 7.4 mg/day) and low for some ziprasidone-treated patients (mean dose = 114.2 mg/day). Both agents equally improved psychotic symptoms, and both were generally well tolerated, with ziprasidone demonstrating a lower MDB score and less effect on prolactin and weight than risperidone.


Blurring of high-resolution data shows that the effect of intrinsic nucleosome occupancy on transcription factor binding is mostly regional, not local.
Genome wide maps of nucleosome occupancy in yeast have recently been produced through deep sequencing of nuclease-protected DNA. These maps have been obtained from both crosslinked and uncrosslinked chromatin in vivo, and from chromatin assembled from genomic DNA and nucleosomes in vitro. Here, we analyze these maps in combination with existing ChIP-chip data, and with new ChIP-qPCR experiments reported here. We show that the apparent nucleosome density in crosslinked chromatin, when compared to uncrosslinked chromatin, is preferentially increased at transcription factor (TF) binding sites, suggesting a strategy for mapping generic transcription factor binding sites that would not require immunoprecipitation of a particular factor. We also confirm previous conclusions that the intrinsic, sequence dependent binding of nucleosomes helps determine the localization of TF binding sites. However, we find that the association between low nucleosome occupancy and TF binding is typically greater if occupancy at a site is averaged over a 600bp window, rather than using the occupancy at the binding site itself. We have also incorporated intrinsic nucleosome binding occupancies as weights in a computational model for TF binding, and by this measure as well we find better prediction if the high resolution nucleosome occupancy data is averaged over 600bp. We suggest that the intrinsic DNA binding specificity of nucleosomes plays a role in TF binding site selection not so much through the specification of precise nucleosome positions that permit or occlude binding, but rather through the creation of low occupancy regions that can accommodate competition from TFs through rearrangement of nucleosomes.


The effects of iron deficiency on lymphocyte cytokine production and activation: preservation of hepatic iron but not at all cost.
Worldwide, over 40% of children have iron deficiency anaemia, frequently associated with infections. Certain cytokines are involved in both immune activation/response to infection and iron transport/metabolism. We therefore assessed the relations among iron deficiency, cytokine production and lymphocyte activation markers in 142 hospitalized Malawian children. We examined peripheral blood lymphocyte antigens/cytokine production using four- colour flow cytometry and serum transferrin receptor (TfR) levels, an inverse measure of iron status unaffected by acute illness or infection, with an enzyme-linked immunosorbent assay. Wilcoxon rank sum tests and logistic regression analyses (LRA) were performed. Iron deficiency (TfR > or = 10 microg/ml) versus TfR < 10 microg/ml, was associated with higher percentages of lymphocytes producing: (a) induced or spontaneous IL-6 (medians: induced, 15.9% for iron-deficient children versus 8.8% for iron-replete children, P = 0.002; spontaneous, 24.4% versus 13.0%, P < 0.001) and (b) induced IFN-gamma (medians:18.4% versus 12.4%, P = 0.006). The percentages of CD8(+) T cells spontaneously producing IL-6 and of all lymphocytes producing induced TNF-alpha and IFN-gamma in the same cell had the strongest relationships to iron deficiency (b = + 0.0211, P = 0.005 and b = + 0.1158, P = 0.012, respectively, LRA) and were also positively related to the co-expression of the T cell activation markers HLA DR and CD38. Severe iron deficiency (TfR > or = 30 microg/ml) was associated with the percentage of lymphocytes producing induced IL-4 (medians: 0.5% versus 1.6%, P < 0.010). The cytokine patterns associated with iron deficiency in our study would preserve iron stores but also preferentially retain the activation capabilities of T cells, albeit not necessarily other immune cells, until a critical level of iron depletion is reached.


Screening for Viral Pathogens in African Simian Bushmeat Seized at A French Airport.
Illegal bushmeat traffic is an important threat to biodiversity conservation of several endangered species and may contribute to the emergence and spread of infectious diseases in humans. The hunting, manipulation and consumption of wildlife-based products, especially those of primate origin, may be a threat to human health; however, few studies have investigated the role of bushmeat trade and consumption as a potential source of human infections to date. In this study, we report the screening of viral pathogens in African simian game seized by French customs at Toulouse Blagnac Airport. Epifluorescence microscopy revealed the presence of virus-like particles in the samples, and further metagenomic sequencing of the DNA and RNA viromes confirmed the presence of sequences related to the Siphoviridae, Myoviridae and Podoviridae bacteriophage families; some of them infecting bacterial hosts that could be potentially pathogenic for humans. To increase the sensitivity of detection, twelve pan-generic PCRs targeting several viral zoonoses were performed, but no positive signal was detected. A large-scale inventory of bacteria, viruses and parasites is urgently needed to globally assess the risk for human health of the trade, manipulation and consumption of wildlife-related bushmeat.


Equivalence trials in SLE research: issues to consider.
In contrast to the objective of most clinical trials, which is to demonstrate superiority of an experimental treatment over a standard or placebo, the aim of an equivalence trial is to show that two treatments are equivalent in outcome or only marginally different. This would be of interest when an experimental treatment offers advantages such as reduced toxicity, ease of administration, or cost relative to the standard. Demonstrating equivalence may also be a goal when evaluating the safety of certain drugs because similarity in the risks of an adverse event in subjects exposed and unexposed to the drug is an indication of its safety. The classical formulation of the null hypothesis of treatment equality that is used in superiority trials is not applicable to equivalence trials because absolute equivalence between treatment groups cannot be proven. The strategy in equivalence trials is to define a maximum difference between treatment groups that is clinically acceptable and then assess whether there is sufficient evidence from the trial to conclude that the true treatment difference is within this acceptable range. In this paper, we discuss issues surrounding the planning, conduct, and analysis of equivalence trials in the context of SLE, with examples from the SELENA study.


Current trends in cannulation and neuroprotection during surgery of the aortic arch in Europe.
To conduct a survey across European cardiac centres to evaluate the methods used for cerebral protection during aortic surgery involving the aortic arch. All European centres were contacted and surgeons were requested to fill out a short, comprehensive questionnaire on an internet-based platform. One-third of more than 400 contacted centres completed the survey correctly. The most preferred site for arterial cannulation is the subclavian-axillary, both in acute and chronic presentation. The femoral artery is still frequently used in the acute condition, while the ascending aorta is a frequent second choice in the case of chronic presentation. Bilateral antegrade brain perfusion is chosen by the majority of centres (2/3 of cases), while retrograde perfusion or circulatory arrest is very seldom used and almost exclusively in acute clinical presentation. The same pumping system of the cardio pulmonary bypass is most of the time used for selective cerebral perfusion, and the perfusate temperature is usually maintained between 22 and 26°C. One-third of the centres use lower temperatures. Perfusate flow and pressure are fairly consistent among centres in the range of 10-15 ml/kg and 60 mmHg, respectively. In 60% of cases, barbiturates are added for cerebral protection, while visceral perfusion still receives little attention. Regarding cerebral monitoring, there is a general tendency to use near-infrared spectroscopy associated with bilateral radial pressure measurement. These data represent a snapshot of the strategies used for cerebral protection during major aortic surgery in current practice, and may serve as a reference for standardization and refinement of different approaches.


Patterning the vertebrate head: murine Hox 2 genes mark distinct subpopulations of premigratory and migrating cranial neural crest.
The structures of the face in vertebrates are largely derived from neural crest. There is some evidence to suggest that the form of the facial pattern is determined by the crest, and that it is specified before migration as to the structures that is is able to form. The neural crest is able to control the form of surrounding, non-neural crest tissues by an instructive interaction. Some of this cranial crest is derived from a region of the hindbrain that expresses Hox 2 homeobox genes in an overlapping and segment-restricted pattern. We have found that neurogenic and mesenchymal neural crest expresses Hox 2 genes from its point of origin beside the neural plate, during migration and after migration has ceased and that rhombomeres 3 and 5 do not have any expressing neural crest beside them. Each branchial arch expresses a different combination or code of Hox genes in a segment-restricted way. The surface ectoderm over the arches initially does not express Hox genes, and later adopts an expression pattern that reflects that of neural crest that has come to underlie it. We suggest that initially the neural plate and neural crest are spatially specified, while the surface ectoderm is unpatterned. Subsequently some positional information could be transferred to the surface ectoderm as a result of an interaction with the neural crest. Given that the role of the homologous genes in insects is position specification, and that neural crest is imprinted before migration, we suggest that Hox 2 genes are providing part of this positional information to the neural crest and hence are involved in patterning the structures of the branchial arches.


Outcome of bronchoscopic biopsies in the University of Benin Teaching Hospital.
Our study was done to evaluate our bronchoscopic techniques, sizes and diagnostic yield. This was a retrospective study comprising all cases of bronchial biopsies done in the University of Benin Teaching Hospital from 2007 to 2011. All patients who had flexible bronchoscopy under general anaesthesia during the period under review where enrolled in the study. There were a total of 16 patients: Nine males and seven females, with a mean age of 46.9 years. The main indications were cough (87.5%), weight loss (62.5%), X-ray findings of a chest lesion (87.5%), chest pain (62.5%), difficulty with breathing (31.3%) and massive haemoptysis (25%). Histology results showed inadequate samples in six and Bronchogenic carcinoma in four patients. The histology was pivotal in eight patients. Bronchoscopic biopsies are fraught with problems and other clinical investigative tools would certainly be important in improving the results.


Fluctuation of quantitative values on acquisition time and the reconstruction conditions in 99mTc-SPECT.
This study aims to carry out a quantitative analysis with high reproducibility using single-photon emission computed tomography/computed tomography (SPECT/CT); we investigated the optimum parameters for the acquisition and the reconstruction. SPECT images were acquired with varying time per view using SPECT phantom (JS-10) and the body phantom of National Electrical Manufacturers Association and International Electrotechnical Commission (Body-phantom), respectively. For the image reconstruction condition, we changed the product of subset and iteration (SI product) and the Gaussian filter using a three-dimensional ordered subset expectation maximization. A combination of no scattering correction and no attenuation correction (SC-/AC-) and a combination of scattering correction and attenuation correction by CT images (SC+/AC+) were performed. The dose linearity, the recovery coefficient, the scatter ratio, and the coefficient of variation were evaluated using JS-10. Using Body-phantom, contrast-to-noise ratios of the hot spheres (13, 17 mm) were calculated. Moreover, the change in the maximum standardized uptake value (SUVmax) and the average SUV (SUVmean) were evaluated for each sphere. From the evaluation results using the JS-10, dose linearity, recovery coefficient, scatter ratio, and coefficient of variation were all good when time per view was 50-150 s, the Gaussian filter was 8-12 mm, and the SI product was 150. From the evaluation results using Body-phantom, comparing the Gaussian filter with 8 mm and 12 mm, the contrast-to-noise ratio was better for 12 mm and the error rate to the change of the scan-time was up to 3.7%. However, SUVmax and SUVmean using 8 mm were closer to the design value of the phantom. It is necessary that Quantitative SPECT be acquired at 50 s or more per view per detection, reconstructed using a three-dimensional ordered subset expectation maximization with SC+/AC+, the SI product is 150 times, and the Gaussian Filter is 8-12 mm. This suggested that the quantitative analysis would be carried out with good reproducibility.


Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes.
SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro. First, the localization of SIRT6 and proliferation cell nuclear antigen (PCNA) in human cartilages was examined by immunohistochemistry. Next, SIRT6 was depleted by RNA interference (RNAi), and the effect of SIRT6 depletion on changes in gene expression, protein levels, proliferation, and senescence in human chondrocytes was assessed. Furthermore, to detect DNA damage and telomere dysfunction, γH2AX foci and telomere dysfunction-induced foci (TIFs) were examined using immunofluorescence microscopy. The protein levels of two mediators for DNA damage induced-senescence, p16 and p21, were examined by western blotting. Immunohistochemical analysis showed SIRT6 was preferentially expressed in the superficial zone chondrocytes and PCNA-positive cluster-forming chondrocytes in the osteoarthritic cartilage tissue samples. Real-time PCR analysis showed that matrix metalloproteinase 1 (MMP-1) and MMP-13 mRNA were significantly increased by SIRT6 inhibition. Moreover, SIRT6 inhibition significantly reduced proliferation and increased senescence associated β-galactosidase (SA-β-Gal)-positive chondrocytes; it also led to increased p16 levels. Immunofluorescence microscopy showed that γH2AX foci and TIFs were increased by SIRT6 inhibition. Depletion of SIRT6 in human chondrocytes caused increased DNA damage and telomere dysfunction, and subsequent premature senescence. These findings suggest that SIRT6 plays an important role in the regulation of senescence of human chondrocytes.


Cryptic Eimeria genotypes are common across the southern but not northern hemisphere.
The phylum Apicomplexa includes parasites of medical, zoonotic and veterinary significance. Understanding the global distribution and genetic diversity of these protozoa is of fundamental importance for efficient, robust and long-lasting methods of control. Eimeria spp. cause intestinal coccidiosis in all major livestock animals and are the most important parasites of domestic chickens in terms of both economic impact and animal welfare. Despite having significant negative impacts on the efficiency of food production, many fundamental questions relating to the global distribution and genetic variation of Eimeria spp. remain largely unanswered. Here, we provide the broadest map yet of Eimeria occurrence for domestic chickens, confirming that all the known species (Eimeria acervulina, Eimeria brunetti, Eimeria maxima, Eimeria mitis, Eimeria necatrix, Eimeria praecox, Eimeria tenella) are present in all six continents where chickens are found (including 21 countries). Analysis of 248 internal transcribed spacer sequences derived from 17 countries provided evidence of possible allopatric diversity for species such as E. tenella (FST values ⩽0.34) but not E. acervulina and E. mitis, and highlighted a trend towards widespread genetic variance. We found that three genetic variants described previously only in Australia and southern Africa (operational taxonomic units x, y and z) have a wide distribution across the southern, but not the northern hemisphere. While the drivers for such a polarised distribution of these operational taxonomic unit genotypes remains unclear, the occurrence of genetically variant Eimeria may pose a risk to food security and animal welfare in Europe and North America should these parasites spread to the northern hemisphere.


Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells: implications for glaucoma pathogenesis.
Increasing evidence suggests oxidative damage as a key factor contributing to the failure of the conventional outflow pathway tissue to maintain appropriate levels of intraocular pressure, and thus increase the risk for developing glaucoma, a late-onset disease which is the second leading cause of permanent blindness worldwide. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors, including oxidative stress. Here, we have monitored, by using different methodologies (LC3-I to LC3-II turnover, tfLC3, and Cyto ID), the induction of autophagy and autophagy flux in TM cells subjected to a normobaric hyperoxic model of mild chronic oxidative stress. Our data indicate the MTOR-mediated activation of autophagy and nuclear translocation of TFEB in oxidatively stressed TM cells, as well as the role of autophagy in the occurrence of SA-GLB1/SA-β-gal. Concomitant with the activation of the autophagic pathway, TM cells grown under oxidative stress conditions displayed, however, reduced cathepsin (CTS) activities, reduced lysosomal acidification and impaired CTSB proteolytic maturation, resulting in decreased autophagic flux. We propose that diminished autophagic flux induced by oxidative stress might represent one of the factors leading to progressive failure of cellular TM function with age and contribute to the pathogenesis of primary open angle glaucoma.


The bifunctional DCOH protein binds to HNF1 independently of its 4-alpha-carbinolamine dehydratase activity.
HNF1 is a liver enriched atypical homeoprotein isolated from vertebrates which is involved in the transcriptional activation of liver, kidney, intestine and pancreas specific genes. HNF1 contains an N-terminal dimerisation and a POU-like domain both essential together with the homeodomain for DNA specific recognition. Using the yeast two-hybrid system we searched for proteins interacting with HNF1. We repeatedly obtained cDNA clones encoding DCOH/4-alpha-carbinolamine dehydratase, an enzyme involved in the oxidation of aromatic amino acids that was shown to bind to and stabilise HNF1 dimers. Using the yeast system, we show that the enzymatic activity of DCOH is not essential for HNF1 binding and that the HNF1 dimerisation domain is sufficient for DCOH binding. Furthermore we demonstrate that both proteins co-localise in co-transfected cells.


Fractional-Order SEIQRDP Model for Simulating the Dynamics of COVID-19 Epidemic.
Goal: Coronavirus disease (COVID-19) is a contagious disease caused by a newly discovered coronavirus, initially identified in the mainland of China, late December 2019. COVID-19 has been confirmed as a higher infectious disease that can spread quickly in a community population depending on the number of susceptible and infected cases and also depending on their movement in the community. Since January 2020, COVID-19 has reached out to many countries worldwide, and the number of daily cases remains to increase rapidly. Method: Several mathematical and statistical models have been developed to understand, track, and forecast the trend of the virus spread. Susceptible-Exposed-Infected-Quarantined-Recovered-Death-Insusceptible (SEIQRDP) model is one of the most promising epidemiological models that has been suggested for estimating the transmissibility of the COVID-19. In the present study, we propose a fractional-order SEIQRDP model to analyze the COVID-19 pandemic. In the recent decade, it has proven that many aspects in many domains can be described very successfully using fractional order differential equations. Accordingly, the Fractional-order paradigm offers a flexible, appropriate, and reliable framework for pandemic growth characterization. In fact, due to its non-locality properties, a fractional-order operator takes into consideration the variables' memory effect, and hence, it takes into account the sub-diffusion process of confirmed and recovered cases. Results-The validation of the studied fractional-order model using real COVID-19 data for different regions in China, Italy, and France show the potential of the proposed paradigm in predicting and understanding the pandemic dynamic. Conclusions: Fractional-order epidemiological models might play an important role in understanding and predicting the spread of the COVID-19, also providing relevant guidelines for controlling the pandemic.


Dietary requirements of rainbow trout for tryptophan, lysine and arginine determined by growth and biochemical measurements.
Three separate studies were performed to determine the dietary requirements of rainbow troutSalmo gairdneri for tryptophan (Trp), lysine (Lys) and arginine (Arg) from both growth and biochemical data. The growth studies were carried out over a 12 week period. From graphical plots of % mean weight gain against % amino acid in diet the following requirement values were obtained, Trp 0.25% diet (0.4% dietary crude protein); Lys 1.9% diet (4.3% dietary protein); and Arg 1.6-1.8% diet (3.6-4% dietary protein). Plasma and liver amino acid concentrations measured 20h after feeding did not prove useful for determination of requirement values. Hepatic activities of Trp pyrrolase (TP), Lys α ketoglutarate reductase (LKGR) and arginase were not significantly affected by varying levels of Trp, Lys and Arg respectively in the diet. TP has a cytosolic location and a Km of 0.2 mM for Trp; LKGR is mitochondrial and the Km for Lys is 7.3 mM; arginase is also mitochondrial and has a Km of 4.9 mM for arginine. Measurements of expired(14)CO2, after injection of a tracer dose of(14)C amino acid, did allow estimates of requirement levels to be made. The values obtained from the oxidation studies reinforced the values obtained from the growth data but were not precise enough to justify using this method on its own.


P-selectin glycoprotein ligand 1 therapy ameliorates established collagen-induced arthritis in DBA/1 mice partly through the suppression of tumour necrosis factor.
We investigated the therapeutic potential of P-selectin glycoprotein ligand (PSGL)-1 in established collagen-induced arthritis (CIA) in DBA/1 mice. PSGL-1 is the high-affinity specific ligand for P-selectin and is thus important in cell recruitment to inflammatory sites. I-316 PSGL-1 or rPSGL-1Ig fusion protein were administered to mice after the onset of clinical arthritis for 10 days, and the effect of treatment on both clinical and histopathological progression of disease was studied. It was found that both PSGL-1 biologicals effectively suppressed progression of clinical arthritis, and this was accompanied by protection against damage of joint tissues. We sought to investigate a mechanism underlying the effect of rPSGL-1Ig on the reduction of clinical arthritis. Blockade of PSGL-1/P-selectin interaction blocks recruitment of leucocytes, thus we observed a notable reduction in viable cell numbers of synoviocytes from rPSGL-1Ig treated mice. In view of this finding we suspected an effect of treatment on the production of pro-inflammatory mediators such as bioactive tumour necrosis factor-alpha (TNF) in synovial membrane ex vivo cell cultures. Production of TNF was reduced in arthritic mice that had been treated with rPSGL-1Ig. To further investigate the mechanism of rPSGL-1Ig, we explored the possibility that PSGL-1 might also have a direct signalling effect on TNF release from inflammatory cells. Thus synoviocyte cultures from arthritic mice were incubated with rPSGL-1Ig. A significant reduction in the spontaneous bioactive TNF release from these cultures was noted. We therefore confirmed these surprising findings using cultures of a mouse macrophage like cell line RAW 264.7, stimulated by LPS. Our results indicate that both forms of PSGL-1 have significant therapeutic effects in CIA murine model of RA. The mechanism of action involves reduced cellularity of synovium as anticipated, along with a reduction in TNF production from inflammatory cells in the synovium. The latter mechanism needs further mechanistic analysis.


Non-GVHD ocular complications after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT.
Non-graft-vs.-host disease (non-GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT), but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment, and ocular toxicities associated with medications. We have summarized incidence, risk factors, screening, prevention and treatment of individual complicastions and generated evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical symptoms, signs and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplant physicians and ophthalmologists should be knowledgeable of non-GVHD ocular complications and provide comprehensive collaborative team care.


Genomic and experimental evidence for multiple metabolic functions in the RidA/YjgF/YER057c/UK114 (Rid) protein family.
It is now recognized that enzymatic or chemical side-reactions can convert normal metabolites to useless or toxic ones and that a suite of enzymes exists to mitigate such metabolite damage. Examples are the reactive imine/enamine intermediates produced by threonine dehydratase, which damage the pyridoxal 5'-phosphate cofactor of various enzymes causing inactivation. This damage is pre-empted by RidA proteins, which hydrolyze the imines before they do harm. RidA proteins belong to the YjgF/YER057c/UK114 family (here renamed the Rid family). Most other members of this diverse and ubiquitous family lack defined functions. Phylogenetic analysis divided the Rid family into a widely distributed, apparently archetypal RidA subfamily and seven other subfamilies (Rid1 to Rid7) that are largely confined to bacteria and often co-occur in the same organism with RidA and each other. The Rid1 to Rid3 subfamilies, but not the Rid4 to Rid7 subfamilies, have a conserved arginine residue that, in RidA proteins, is essential for imine-hydrolyzing activity. Analysis of the chromosomal context of bacterial RidA genes revealed clustering with genes for threonine dehydratase and other pyridoxal 5'-phosphate-dependent enzymes, which fits with the known RidA imine hydrolase activity. Clustering was also evident between Rid family genes and genes specifying FAD-dependent amine oxidases or enzymes of carbamoyl phosphate metabolism. Biochemical assays showed that Salmonella enterica RidA and Rid2, but not Rid7, can hydrolyze imines generated by amino acid oxidase. Genetic tests indicated that carbamoyl phosphate overproduction is toxic to S. enterica cells lacking RidA, and metabolomic profiling of Rid knockout strains showed ten-fold accumulation of the carbamoyl phosphate-related metabolite dihydroorotate. Like the archetypal RidA subfamily, the Rid2, and probably the Rid1 and Rid3 subfamilies, have imine-hydrolyzing activity and can pre-empt damage from imines formed by amine oxidases as well as by pyridoxal 5'-phosphate enzymes. The RidA subfamily has an additional damage pre-emption role in carbamoyl phosphate metabolism that has yet to be biochemically defined. Finally, the Rid4 to Rid7 subfamilies appear not to hydrolyze imines and thus remain mysterious.


Joint profiling of chromatin accessibility and CAR-T integration site analysis at population and single-cell levels.
Chimeric antigen receptor (CAR)-T immunotherapy has yielded impressive results in several B cell malignancies, establishing itself as a powerful means to redirect the natural properties of T lymphocytes. In this strategy, the T cell genome is modified by the integration of lentiviral vectors encoding CAR that direct tumor cell killing. However, this therapeutic approach is often limited by the extent of CAR-T cell expansion in vivo. A major outstanding question is whether or not CAR-T integration itself enhances the proliferative competence of individual T cells by rewiring their regulatory landscape. To address this question, it is critical to define the identity of an individual CAR-T cell and simultaneously chart where the CAR-T vector integrates into the genome. Here, we report the development of a method called EpiVIA (https://github.com/VahediLab/epiVIA) for the joint profiling of the chromatin accessibility and lentiviral integration site analysis at the population and single-cell levels. We validate our technique in clonal cells with previously defined integration sites and further demonstrate the ability to measure lentiviral integration sites and chromatin accessibility of host and viral genomes at the single-cell resolution in CAR-T cells. We anticipate that EpiVIA will enable the single-cell deconstruction of gene regulation during CAR-T therapy, leading to the discovery of cellular factors associated with durable treatment.


Synergistic effect of IL-3 and IL-6 on highly enriched murine hemopoietic progenitors.
It has been reported that interleukin 6 (IL-6) acts on hemopoietic stem cells in synergism with interleukin 3 (IL-3), but it has not yet been clarified whether IL-6 acts directly on the stem cells or not. To investigate the mechanism of the synergism between IL-3 and IL-6, we sorted hemopoietic stem cells from untreated murine bone marrow cells using a two-laser fluorescence-activated cell sorter (FACS). Cells negative for the lymphohemopoietic lineage (lineage-negative, Lin-), with a high affinity to wheat germ agglutinin (WGA+), and showing a low expression of Thy-1 antigen (Thy-1low) were sorted and analyzed by in vitro and in vivo colony formation. This fraction was 0.4% of the total mononuclear bone marrow cells. Approximately 25% of these Lin-WGA+Thy-1low cells showed in vitro colony formation, whereas approximately 1% of them formed day-8 and day-12 spleen colonies. Thus, it appears that the Lin-WGA+Thy-1low cells were a highly enriched stem cell population. By FACS clone sorting, single cells were isolated from the enriched stem cell fraction and cultured in semisolid or liquid culture systems. Addition of IL-6 to methylcellulose medium containing IL-3 did not significantly increase the number of colonies. It is thus suggested that the target cells of IL-3 and IL-6 are the same as those of IL-3. The secondary colony-forming ability of primary colonies that developed in the presence of IL-6 and IL-3 was higher than that of colonies formed in the presence of IL-3 alone. In correspondence with this finding, the numbers of myeloid colonies and spleen colony-forming units (CFU-S) were increased by the incubation of these sorted cells for 7 days with IL-6 and IL-3 when compared with the effect of IL-3 alone. Therefore, it is concluded that IL-6 acts directly on hemopoietic stem cells to enhance their proliferation.


[Internet and cell phone addiction: passing fad or disorder?].
The Information and Communication Technologies (ICT) generate new styles of meeting people or connecting with friends or strangers. In this context, the internet and the mobile phone deserve special attention. This article deals with the maladaptive use of these technologies. By reviewing the literature published between 1991 and 2005 and indexed in the databases of PsycINFO, Medline, Psicodoc, IME, and ISOC, we aim to determine whether maladaptive use of these technologies can be considered a mental disorder, and if so, of which type. We describe the psychological phenomena of maladaptive use of the internet and mobile phones, we review research on prevalence and possible risk groups, and finally we discuss some of the criticisms made with regard to the existence and classification of this disorder. It is concluded that excessive use of the internet can lead to a mental disorder of the addictive type, which can particularly affect individuals with special emotional needs, as well as adolescents and young adults. Among specific applications of the internet, a major risk is found for the use of communicative and synchronic applications, such as chats and online role games, since they permit hyperpersonal communication, playing with different identities, and projections and dissociation without consequences in real life. Furthermore, the internet can play an important role in the development and maintenance of other addictions, such as pathological gambling and sex addiction. In contrast to the case of the internet, maladaptive use of mobile phones may be considered abuse, but not addiction, since their use does not lead to the rapid emotional changes or the playing with identities that can take place in chats and online role games.


Chaga mushroom extract inhibits oxidative DNA damage in human lymphocytes as assessed by comet assay.
The Chaga mushroom (Inonotus obliquus) is claimed to have beneficial properties for human health, such as anti-bacterial, anti-allergic, anti-inflammatory and antioxidant activities. The antioxidant effects of the mushroom may be partly explained by protection of cell components against free radicals. We evaluated the effect of aqueous Chaga mushroom extracts for their potential for protecting against oxidative damage to DNA in human lymphocytes. Cells were pretreated with various concentrations (10, 50, 100 and 500 microg/mL) of the extract for 1 h at 37 degrees C. Cells were then treated with 100 microM of H2O2 for 5 min as an oxidative stress. Evaluation of oxidative damage was performed using single-cell gel electrophoresis for DNA fragmentation (Comet assay). Using image analysis, the degree of DNA damage was evaluated as the DNA tail moment. Cells pretreated with Chaga extract showed over 40% reduction in DNA fragmentation compared with the positive control (100 micromol H2O2 treatment). Thus, Chaga mushroom treatment affords cellular protection against endogenous DNA damage produced by H2O2.


Current practices for postoperative pain management in Europe and the potential role of the fentanyl HCl iontophoretic transdermal system.
Survey results continue to reveal that postoperative pain is insufficiently managed throughout Europe and the rest of the world. However, the efficient use of existing resources, as well as the introduction of novel technologies, may aid in its improvement. Use of an acute pain service has the potential to improve pain management through specialized patient care and utilization of effective analgesic techniques. Multimodal analgesic techniques, which include adjuvant non-opioids and/or regional analgesic techniques, can provide effective analgesia and reduce the amount of systemic opioids (or obviate the need) for postoperative pain management. Patient-controlled analgesia modalities may also offer improvements to pain management, as in practice they provide pain relief superior to the intermittent administration of bolus doses of opioids. A novel patient-controlled analgesia modality that has been approved by the European Medicines Evaluation Agency (EMEA) for the treatment of acute, moderate-to-severe pain is the needle-free, pre-programmed fentanyl HCl iontophoretic transdermal system. This system was shown in a recent US clinical trial to be comparable in efficacy to a standard regimen of morphine intravenous patient-controlled analgesia. Adverse events associated with the use of the fentanyl iontophoretic transdermal system are generally similar to those experienced by patients using intravenous morphine patient-controlled analgesia. Considerations regarding the selection of patients for treatment with the fentanyl iontophoretic transdermal system are similar to those with other patient-controlled analgesia modalities; sufficient upper limb mobility and alertness are required to operate the system. Utilization of the fentanyl iontophoretic transdermal system, together with the guidance of an effective acute pain service, may lead to improvements in postoperative pain management.


Plasmonically enhanced hot electron based photovoltaic device.
Hot electron photovoltaics is emerging as a candidate for low cost and ultra thin solar cells. Plasmonic means can be utilized to significantly boost device efficiency. We separately form the tunneling metal-insulator-metal (MIM) junction for electron collection and the plasmon exciting MIM structure on top of each other, which provides high flexibility in plasmonic design and tunneling MIM design separately. We demonstrate close to one order of magnitude enhancement in the short circuit current at the resonance wavelengths.