Stationary Wavelet-Fourier Entropy and Kernel Extreme Learning for Bearing Multi-Fault Diagnosis.
Bearing fault diagnosis methods play an important role in rotating machine health monitoring. In recent years, various intelligent fault diagnosis methods have been proposed, which are mainly based on the features extraction method combined with either shallow or deep learning methods. During the last few years, Shannon entropy features have been widely used in machine health monitoring, improving the accuracy of the bearing fault diagnosis process. Therefore, in this paper, we consider the combination of multi-scale stationary wavelet packet analysis with the Fourier amplitude spectrum to obtain a new discriminative Shannon entropy feature that we call stationary wavelet packet Fourier entropy (SWPFE). Features extracted by our SWPFE method are then passed onto a shallow kernel extreme learning machine (KELM) classifier to diagnose bearing failure types with different severities. The proposed method was applied on two experimental vibration signal databases of a rolling element bearing and compared to two recently proposed methods called stationary wavelet packet permutation entropy (SWPPE) and stationary wavelet packet dispersion entropy (SWPPE). Based on our results, we can say that the proposed method is able to achieve better accuracy levels than both the SWPPE and SWPDE methods using fewer failure features. Further, as our method does not require any hyperparameter calibration step, it is less dependent on user experience/expertise.


Central nervous system neurodegeneration and tinnitus: a clinical experience. Part I: Diagnosis.
In an evolving clinical experience since 1979, the medical significance of the symptom of tinnitus has been identified as a "soft" sign of neurodegeneration (ND) in the central nervous system (CNS) in a particular subset of tinnitus patients diagnosed with a predominantly central-type, severe, disabling, subjective idiopathic tinnitus. To highlight this experience, a retrospective review and analysis of consecutive tinnitus patients (N = 96) was conducted. Ninety-six tinnitus patients (ages 22-90 years) were seen in neurotological consultation from November 1, 2005, to June 30, 2007, all of whom had subjective idiopathic tinnitus of the severe disabling type (SIT). Of these 96 patients, 54 had SIT of the predominantly central type and of these, 18 (ages 39-75 years) were recommended for nuclear medicine imaging (single-photon emission computed tomography [SPECT] and fluorodeoxyglucose-positron emission tomography/computed tomography [FDG-PET/CT]). Patient selection for nuclear medicine imaging fulfilled the criteria of a medical-audiological ND tinnitus profile: completion of a patient protocol that diagnosed a predominantly central-type, severe, disabling, subjective, idiopathic tinnitus lasting in excess of 1 year, and failure of existing modalities of treatment attempting tinnitus relief. In 16 of the 18 patients, objective evidence of ND was reported in multiple neural substrates of brain obtained with SPECT or FDG-PET/CT of brain. Classification of CNS ND and tinnitus differentiated between (1) ND of nonspecific or unknown etiology; (2) ND manifested by perfusion asymmetries in brain associated with ischemia (n = 11/18); and (3) neurodegenerative CNS disease consistent with nuclear medicine criteria for senile dementia of the Alzheimer's type (n = 5/18). The diagnosis has been associated with cerebrovascular disease (n = 16/18). The identification of neurodegenerative CNS disease in a selected cohort of patients with subjective idiopathic tinnitus as a soft sign of such CNS disease has implications for diagnosis and treatment.


How accurately do different computer-based texture characterization methods predict material surface coarseness? A guideline for effective online inspection.
The growing industrialization has emphasized the need for high-performance computer-based inspection methods. Here, we investigated the performance of four major computer-based texture characterization methods in the prediction of visually perceived and actual surface coarseness of real materials. Gray level co-occurrence matrix (GLCM), distance-dependent edge frequency (DDEF), fractal dimension (FD), and histogram skewness (SK) were used as the methods. A novel collection of real materials consisting of 20 sandpapers with high, medium, and low coarseness levels was employed. The results revealed that at high coarseness level the most precise prediction of actual surface coarseness was made by GLCM and SK, while in the prediction of visual coarseness all the methods worked similarly effectively. Perfect correlations were observed between GLCM, FD, and SK at visual and also actual coarseness at medium coarseness level. At low coarseness level, SK and DDEF acceptably predicted visual and actual coarseness, respectively. The image resolution impact on performance of the computer-based methods was found to be substantial. Results of the research present a guideline for choosing the best computer-based method as a viable substitute for the human observer in online inspections of materials' texture.


Positive end-expiratory pressure as a novel method to thwart CO2 leakage from capnothorax in robotic-assisted thoracoscopic surgery.
Capnography and end tidal CO2 (EtCO2) aids the anaesthesiologist in diagnosing problems during all phases of general anaesthesia. Negative arterial to end-tidal carbon-dioxide gradient during anaesthesia has been reported in various conditions including pregnancy, infants and inadvertent exogenous addition of carbon dioxide (CO2) to the expired gas in case of thoracoscopic procedures with iatrogenic injury to lung parenchyma/bronchial tree. Thus, airway injury or intentional opening of airway as a part of surgical step can be diagnosed using a negative arterial and end tidal CO2 gradient. Higher optimal PEEP can be used as a splint across the bronchial cuff in one-lung ventilation which prevents leak from capnothorax and decrease inadvertent entry of CO2 in to the expired gases which erroneously increase arteriolar to end tidal CO2 gradient.


A multicountry randomized controlled trial of comprehensive maternal nutrition supplementation initiated before conception: the Women First trial.
Reported benefits of maternal nutrition supplements commenced during pregnancy in low-resource populations have typically been quite limited. This study tested the effects on newborn size, especially length, of commencing nutrition supplements for women in low-resource populations ≥3 mo before conception (Arm 1), compared with the same supplement commenced late in the first trimester of pregnancy (Arm 2) or not at all (control Arm 3). Women First was a 3-arm individualized randomized controlled trial (RCT). The intervention was a lipid-based micronutrient supplement; a protein-energy supplement was also provided if maternal body mass index (kg/m2) was <20 or gestational weight gain was less than recommendations. Study sites were in rural locations of the Democratic Republic of the Congo (DRC), Guatemala, India, and Pakistan. The primary outcome was length-for-age z score (LAZ), with all anthropometry obtained <48 h post delivery. Because gestational ages were unavailable in DRC, outcomes were determined for all 4 sites from WHO newborn standards (non-gestational-age-adjusted, NGAA) as well as INTERGROWTH-21st fetal standards (3 sites, gestational age-adjusted, GAA). A total of 7387 nonpregnant women were randomly assigned, yielding 2451 births with NGAA primary outcomes and 1465 with GAA outcomes. Mean LAZ and other outcomes did not differ between Arm 1 and Arm 2 using either NGAA or GAA. Mean LAZ (NGAA) for Arm 1 was greater than for Arm 3 (effect size: +0.19; 95% CI: 0.08, 0.30, P = 0.0008). For GAA outcomes, rates of stunting and small-for-gestational-age were lower in Arm 1 than in Arm 3 (RR: 0.69; 95% CI: 0.49, 0.98, P = 0.0361 and RR: 0.78; 95% CI: 0.70, 0.88, P < 0.001, respectively). Rates of preterm birth did not differ among arms. In low-resource populations, benefits on fetal growth-related birth outcomes were derived from nutrition supplements commenced before conception or late in the first trimester. This trial was registered at clinicaltrials.gov as NCT01883193.


Keratin 20 helps maintain intermediate filament organization in intestinal epithelia.
Of the >20 epithelial keratins, keratin 20 (K20) has an unusual distribution and is poorly studied. We began to address K20 function, by expressing human wild-type and Arg80-->His (R80H) genomic (18 kb) and cDNA K20 in cells and mice. Arg80 of K20 is conserved in most keratins, and its mutation in epidermal keratins causes several skin diseases. R80H but not wild-type K20 generates disrupted keratin filaments in transfected cells. Transgenic mice that overexpress K20 R80H have collapsed filaments in small intestinal villus regions, when expressed at moderate levels, whereas wild-type K20-overexpressing mice have normal keratin networks. Overexpressed K20 maintains its normal distribution in several tissues, but not in the pancreas and stomach, without causing any tissue abnormalities. Hence, K20 pancreatic and gastric expression is regulated outside the 18-kb region. Cross-breeding of wild-type or R80H K20 mice with mice that overexpress wild-type K18 or K18 that is mutated at the conserved K20 Arg80-equivalent residue show that K20 plays an additive and compensatory role with K18 in maintaining keratin filament organization in the intestine. Our data suggest the presence of unique regulatory domains for pancreatic and gastric K20 expression and support a significant role for K20 in maintaining keratin filaments in intestinal epithelia.


Epitope tagging for tracking elastin-like polypeptides.
Elastin-like polypeptides (ELPs) are a class of biocompatible, non-immunogenic and crosslinkable biomaterials that offer promise for use as an injectable scaffold for cartilage repair. In this study, an oligohistidine (His(6)) epitope tag was incorporated at the N-terminus of an ELP using recombinant DNA techniques to permit tracking without compromising on material biocompatibility. His(6)-tagged ELPs were successfully detected by Western blot analysis and quantified by ELISAs following digestion with trypsin. The mass of His(6) tagged ELP fragments freed from a crosslinked ELP hydrogel after digestion with trypsin correlated highly with hydrogel weight loss, providing evidence of the tag's capability to enable tracking of enzymatic degradation of the ELP hydrogel. The His(6) tag also facilitated recognition of crosslinked ELPs from background staining of articular cartilage. These results suggest that the His(6) epitope tag has the potential to track ELP scaffold loss independently of newly formed tissue mass for evaluating matrix remodeling in vivo.


Self-medication with Antibiotics in a primary care setting in King Khalid University Hospital, Riyadh, Saudi Arabia.
The objectives of this study are to estimate the prevalence of self-medication with antibiotics in King Khalid University Hospital population and evaluate the factors affecting this behavior. This was a cross-sectional study conducted at King Khalid university hospital from April to May 2016. A pretested self-administered questionnaire was handed to a random selection of 519 patients attending the primary care clinics . Data were entered into Microsoft Office Excel 2007 and sent to SPSS version 20 for analysis. Descriptive statistics and logistic regression were applied. The prevalence rate of self-medication with antibiotics was 40.8%. Older patients and males were most likely to use antibiotics without a prescription. The most common illnesses that made patients use antibiotics was upper respiratory tract infections (73.2%). Commercial pharmacies were the major source 82.8%. Only 27.8% patients consulted their physicians for the correct dosage . The previous experience with a similar illness (67.2%) and difficulty in obtaining medical help (29.3%) were the most common reasons for self-administration of antibiotics. Improved health condition (57.8%) was the main reason for stopping the use of antibiotics while lack of improvement in health status led to a shift to another antibiotic in 62.5% of the respondents. The prevalence of using antibiotics without a prescription is relatively high. Proper education of the public on the dangers of the misuse of antibiotics through the media might help to reduce this practice.


Quantitative regional analysis of myocardial wall motion.
This paper presents a new technique for semiautomatic quantification of regional heart function from 2-D echocardiography. It uses a novel left ventricular border tracking algorithm based on shape-space ideas that we have recently described. In this paper, we show how to decompose the tracked output into clinically meaningful segmental parameters (wall excursion and thickening), using what we call a computational interpretational space (CIS). This leads to a quantitative and automatic scoring scheme for endocardial excursion and myocardial thickening. The method is illustrated on data from a patient with a myocardial infarct in the apical anterior/inferior region of the heart and is also assessed in a small retrospective dobutamine stress echocardiography clinical case study.


Structural basis of conformational transitions in the active site and 80's loop in the FK506-binding protein FKBP12.
The extensive set of NMR doublings exhibited by the immunophilin FKBP12 (FK506-binding protein 12) arose from a slow transition to the cis-peptide configuration at Gly89 near the tip of the 80's loop, the site for numerous protein-recognition interactions for both FKBP12 and other FKBP domain proteins. The 80's loop also exhibited linebroadening, indicative of microsecond to millisecond conformational dynamics, but only in the trans-peptide state. The G89A variant shifted the trans-cis peptide equilibrium from 88:12 to 33:67, whereas a proline residue substitution induced fully the cis-peptide configuration. The 80's loop conformation in the G89P crystal structure at 1.50 Å resolution differed from wild-type FKBP12 primarily at residues 88, 89 and 90, and it closely resembled that reported for FKBP52. Structure-based chemical-shift predictions indicated that the microsecond to millisecond dynamics in the 80's loop probably arose from a concerted main chain (ψ88 and ϕ89) torsion angle transition. The indole side chain of Trp59 at the base of the active-site cleft was reoriented ~90o and the adjacent backbone was shifted in the G89P crystal structure. NOE analysis of wild-type FKBP12 demonstrated that this indole populates the perpendicular orientation at 20%. The 15N relaxation analysis was consistent with the indole reorientation occurring in the nanosecond timeframe. Recollection of the G89P crystal data at 1.20 Å resolution revealed a weaker wild-type-like orientation for the indole ring. Differences in the residues that underlie the Trp59 indole ring and altered interactions linking the 50's loop to the active site suggested that reorientation of this ring may be disfavoured in the other six members of the FKBP domain family that bear this active-site tryptophan residue.


Margin-Controlled, Staged Surgical Excision in the Treatment of High-Risk Basal Cell Carcinomas of the Head and Neck Region.
The most common skin cancer is basal cell carcinoma (BCC), and the gold-standard treatment for high-risk tumours is Mohs surgery. However, alternative methods are needed for high-risk tumours in countries where the performance rate of Mohs surgery is low. The objective of this article is to investigate the feasibility, efficacy, and safety of margin-controlled, staged surgical excision (MCSSE) in high-risk tumours as a possible treatment alternative. A retrospective cohort study, including patients diagnosed with high-risk BCC in the head and neck region and treated with MCSSE between 2003 and 2010, was conducted. During the study period 50 tumours in 47 patients were treated, with low adverse event rates and high patient satisfaction rates. Of the 50 tumours, 1 recurred at the 12-month follow-up. Despite the small sample size and relatively short follow-up period, the present study shows that MCSSE might be a feasible alternative for the treatment of high-risk BCCs in institutions where Mohs surgery is not performed. Future studies on long-term recurrence rates are needed.


Retinol-binding protein 4 in neonates born small for gestational age.
Retinol-binding protein 4 (RBP4) is an adipocyte-derived 'signal' that may contribute to the pathogenesis of insulin resistance and Type 2 diabetes. The relationship of RBP4 with insulin resistance and metabolic risk in human beings has been the subject of several studies. Subjects born small for gestational age (SGA) are at risk of insulin resistance and Type 2 diabetes. Though RBP4 could represent an early marker of insulin resistance, to date, none have determined RBP4 in SGA children. Our aim was to measure RBP4 concentrations in cord blood of SGA newborns compared with those in children born with a birth weight appropriate for gestational age (AGA) and to determine whether serum RBP4 levels at birth correlate with insulin sensitivity markers. Sixty-four newborns, 17 born SGA (mean gestational age: 36.4+/-2.1 weeks), and 47 born AGA (mean gestational age: 37.0+/-3.6 weeks) were studied. The main outcome measures included anthropometry, lipid profile, insulin, homeostasis model assessment, quantitative insulin-sensitivity check index, adiponectin, and RBP4. RBP4 concentrations were significantly reduced in SGA newborns (p<0.002). No relationship was found between RBP4 and insulin sensitivity parameters. Stepwise regression analysis revealed that birth weight was the major predictor of RBP4 serum concentrations (p<0.001). RBP4 is reduced in SGA newborns, birth weight representing the major determinant of RBP4 concentrations, and is not related to insulin sensitivity. No significant difference in adiponectin levels and insulin sensitivity markers was found between SGA and AGA neonates.


The interpretation of symptoms of severe dietary restraint.
A recent cognitive-behavioural theory of eating disorders proposes that people with eating disorders interpret symptoms of dietary restraint in terms of control. The primary aim of the present study was to test this hypothesis. A second aim was to test the hypothesis derived from clinical observation that people with eating disorders view these symptoms positively. Forty-four participants meeting DSM-IV criteria for a clinical eating disorder and 80 control participants with no history of an eating disorder completed an ambiguous scenario paradigm and self-report measures of eating disorder features and depression. Patients with eating disorders were significantly more likely to interpret symptoms of dietary control in terms of control, providing support for the cognitive-behavioural theory. There was only partial support for the second hypothesis. The implications for the new cognitive-behavioural theory and therapy are discussed.


Impulsivity and genetic variants in DRD2 and ANKK1 moderate longitudinal associations between sleep problems and overweight from ages 5 to 11.
Short sleep duration and sleep problems increase risks of overweight and weight gain. Few previous studies have examined sleep and weight repeatedly over development. This study examined the associations between yearly reports of sleep problems and weight status from ages 5 to 11. Although, previous studies have shown that inter-individual differences moderate the effect of short sleep duration on weight, it is not known whether inter-individual differences also moderate the effect of sleep problems on weight. We tested how the longitudinal associations between sleep problems and weight status were moderated by impulsivity and genetic variants in DRD2 and ANKK1. Seven-year longitudinal study. A total of 567 children from the Child Development Project for the analysis with impulsivity and 363 for the analysis with genetic variants. Sleep problems and weight status were measured by mothers' reports yearly. Impulsivity was measured by teachers' reports yearly. Six single-nucleotide polymorphisms located in DRD2 and ANKK1 were genotyped. Data were analyzed using multilevel modeling. Higher average levels of sleep deprivation across years were associated with greater increases in overweight (P=0.0024). Sleep problems and overweight were associated at both within-person across time (P<0.0001) and between-person levels (P<0.0001). Impulsivity and two polymorphisms, rs1799978 and rs4245149 in DRD2, moderated the association between sleep problems and overweight; the association was stronger in children who were more impulsive (P=0.0022), in G allele carriers for rs1799978 (P=0.0007) and in A allele carriers for rs4245149 (P=0.0002). This study provided incremental evidence for the influence of sleep problems on weight. Findings of DRD2, ANKK1 and impulsivity are novel; they suggest that reward sensitivity and self-regulatory abilities might modulate the influences of sleep on weight gain. The analysis of polymorphisms was restricted to European Americans and hence the results might not generalize to other populations.


High density lipoproteins (HDLs) and atherosclerosis; the unanswered questions.
The concentration of high density lipoprotein-cholesterol (HDL-C) has been found consistently to be a powerful negative predictor of premature coronary heart disease (CHD) in human prospective population studies. There is also circumstantial evidence from human intervention studies and direct evidence from animal intervention studies that HDLs protect against the development of atherosclerosis. HDLs have several documented functions, although the precise mechanism by which they prevent atherosclerosis remains uncertain. Nor is it known whether the cardioprotective properties of HDL are specific to one or more of the many HDL subpopulations that comprise the HDL fraction in human plasma. Several lifestyle and pharmacological interventions have the capacity to raise the level of HDL-C, although it is not known whether all are equally protective. Indeed, despite the large body of information identifying HDLs as potential therapeutic targets for the prevention of atherosclerosis, there remain many unanswered questions that must be addressed as a matter of urgency before embarking wholesale on HDL-C-raising therapies as strategies to prevent CHD. This review summarises what is known and highlights what we still need to know.


Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion.
The present study was conducted to compare the pharmacokinetics and pharmacodynamics (PD) of paclitaxel between Phase I trials of 3- and 24-h infusions and to determine the most informative pharmacokinetic parameter to describe the PD. Twenty-seven patients were treated in a Phase I study of paclitaxel by a 3-h infusion at one of six doses: 105, 135, 180, 210, 240, and 270 mg/m2. Pharmacokinetic data were obtained from all patients. Paclitaxel concentrations were measured in the plasma and urine using HPLC. The pharmacokinetics and PD were compared with those of a Phase I trial of paclitaxel by a 24-h schedule previously performed. The maximum tolerated dose of paclitaxel by a 3-h infusion was determined to be 240 mg/m2. The major toxicities were granulocytopenia, neuromuscular toxicities, and hypotension. Apparent differences in pharmacodynamic relationships for the change in granulocytes with dose, peak concentration, and areas under the concentration versus time curve were observed between the 3- and 24-h schedules. However, the relationship between the duration of plasma concentration above 0.05 microM and the change in granulocytes could be fitted to the same sigmoid maximum effect model in either schedule (P < 0.01). There were no clear relationships between peripheral neuropathy or hypotension and any pharmacokinetic parameters. The pharmacokinetics and PD of paclitaxel were schedule dependent. The duration of plasma concentration above 0.05 microM could be a common pharmacokinetic parameter predicting granulocytopenia for both schedules.


Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability.
The colorectum and uterine endometrium are the two most commonly affected organs in hereditary nonpolyposis colon cancer (HNPCC), but the genetic basis of organ selection is poorly understood. As tumorigenesis in HNPCC is driven by deficient DNA mismatch repair (MMR), we compared its typical consequence, instability at microsatellite sequences, in colorectal and endometrial cancers from patients with identical predisposing mutations in the MMR genes MLH1 or MSH2. Analysis of non-coding (BAT25, BAT26, and BAT40) and coding mononucleotide repeats (MSH6, MSH3, MLH3, BAX, IGF2R, TGF beta RII, and PTEN), as well as MLH1- and MSH2-linked dinucleotide repeats (D3S1611 and CA7) revealed significant differences, both quantitative and qualitative, between the two tumor types. Whereas colorectal cancers displayed a predominant pattern consisting of instability at the BAT loci (in 89% of tumors), TGF beta RII (73%), dinucleotide repeats (70%), MSH3 (43%), and BAX (30%), no such single pattern was discernible in endometrial cancers. Instead, the pattern was more heterogeneous and involved a lower proportion of unstable markers per tumor (mean 0.27 for endometrial cancers versus 0.45 for colorectal cancers, P < 0.001) and shorter allelic shifts for BAT markers (average 5.1 bp for unstable endometrial cancers versus 9.3 bp for colorectal cancers, P < 0.001). Among the individual putative "target" loci, PTEN instability was associated with endometrial cancers and TGF beta RII instability with colon cancers. The different instability profiles in endometrial and colorectal cancers despite identical genetic predisposition underlines organ-specific differences that may be important determinants of the HNPCC tumor spectrum.


Viremia and AIDS in rhesus macaques after intramuscular inoculation of plasmid DNA encoding full-length SIVmac239.
We have succeeded in stably maintaining the entire genome of SIVmac239 as a plasmid clone. Supercoiled proviral plasmid DNA was inoculated intramuscularly into two adult rhesus macaques and into a neonate. All three animals became viremic and seroconverted. Viral kinetics were followed prospectively by quantitative competitive reverse transcriptase polymerase chain reaction (QC-RT-PCR), measurement of proviral DNA load in peripheral blood mononuclear cells (PBMCs) by PCR, and virus isolation by cocultivation. The infant developed high virus loads and succumbed to AIDS and SIV-associated nephropathy at 10 weeks postinoculation. Both adults are still living but have progressed to AIDS; one adult has also developed severe thrombocytopenia. We conclude that infection through intramuscular inoculation of cloned plasmid DNA encoding the entire proviral genome is reproducible and will provide a useful tool for studying viral pathogenesis.


Targeting Macrophage Histone H3 Modification as a Leishmania Strategy to Dampen the NF-κB/NLRP3-Mediated Inflammatory Response.
Aberrant macrophage activation during intracellular infection generates immunopathologies that can cause severe human morbidity. A better understanding of immune subversion strategies and macrophage phenotypic and functional responses is necessary to design host-directed intervention strategies. Here, we uncover a fine-tuned transcriptional response that is induced in primary and lesional macrophages infected by the parasite Leishmania amazonensis and dampens NF-κB and NLRP3 inflammasome activation. Subversion is amastigote-specific and characterized by a decreased expression of activating and increased expression of de-activating components of these pro-inflammatory pathways, thus revealing a regulatory dichotomy that abrogates the anti-microbial response. Changes in transcript abundance correlate with histone H3K9/14 hypoacetylation and H3K4 hypo-trimethylation in infected primary and lesional macrophages at promoters of NF-κB-related, pro-inflammatory genes. Our results reveal a Leishmania immune subversion strategy targeting host cell epigenetic regulation to establish conditions beneficial for parasite survival and open avenues for host-directed, anti-microbial drug discovery.


Maternal awareness of young children's physical activity: levels and cross-sectional correlates of overestimation.
Factors associated with parental awareness of children's physical activity (PA) levels have not been explored in preschool-aged children. This paper investigates maternal awareness of preschool-aged children's PA levels and determined correlates associated with maternal overestimation of PA. Data from the Southampton Women's Survey, a UK population-based study, were collected March 2006 through June 2009. Daily minutes of moderate-to-vigorous PA (MVPA) were derived using accelerometry in 478 4-year-old children. Mothers who were realistic or overestimated their child's PA were identified. Log-binomial regression was used to analyse correlates of maternal overestimation of PA levels in children whose mothers perceived them to be active (n = 438). 40.8% of children were classified as inactive: 89.7% of these were perceived to be active by their mothers (over-estimators). These mothers were more likely to think their child sometimes lacked skills required to be physically active (RR (95% CI) = 1.29(1.03-1.63)) and their child was more likely to attend nursery full-time (RR = 1.53(1.14-2.04)). They were less likely to have older children at home (RR = 0.71(0.56-0.90)). Almost 90% of mothers of inactive preschool-aged children perceive their child to be active. Nursery-school attendance and having older siblings at home may be important to consider when designing behavioural interventions to increase PA in preschool children.


A mass in the junction of the body and tail of the pancreas with negative IgG4 serology: IgG4-related disease with negative serology.
Autoimmune pancreatitis is an IgG4-related fibroinflammatory condition often associated with obstructive jaundice, as most lesions are located at the head of the pancreas. IgG4 level can help in the diagnosis, but it is normal in nearly 30% of affected patients. A 55-year-old woman presented with a 5-month history of 20-pound unintentional weight loss and intermittent abdominal pain. She had an unremarkable abdominal exam and significant findings included a small, non-mobile rubbery left axillary lymph node. Complete blood count, complete metabolic panel, amylase, anti-smooth muscle antibody, antimitochondrial antibody, carcinoembryonic antigen, Ca 19-9, complement C3 and C4, antinuclear antibody, anti-Smith double-strand antibody, and IgG4 were all within normal limits. CT of the abdomen showed a mass in the junction of the body and tail of the pancreas and endoscopic ultrasound showed it as encasing the splenic artery. Fine-needle aspiration cytology demonstrated follicular hyperplasia, obliterative phlebitis, storiform fibrosis, and negative staining for IgG4 and malignancy. Left axillary lymph node biopsy demonstrated follicular hyperplasia. PET scan revealed hypermetabolic uptake of the pancreas tail, bone marrow, and spleen, as well as diffuse lymphadenopathy. Bone marrow biopsy showed follicular hyperplasia and was negative for malignancy. The patient was started on 40 mg of oral prednisone for possible autoimmune disease. During follow-up, she reported progressive improvement and a repeat PET scan 6 months later showed marked improvement. A normal IgG4 value should not decrease the clinical suspicion of IgG4-related disease. If clinical, histological, and radiological findings coincide, glucocorticoids should be initiated with subsequent follow-up to evaluate for a response.


The plant proteolytic machinery and its role in defence.
The diverse roles of plant proteases in defence responses that are triggered by pathogens or pests are becoming clearer. Some proteases, such as papain in latex, execute the attack on the invading organism. Other proteases seem to be part of a signalling cascade, as indicated by protease inhibitor studies. Such a role has also been suggested for the recently discovered metacaspases and CDR1. Some proteases, such as RCR3, even act in perceiving the invader. These exciting recent reports are probably just the first examples of what lies beneath. More roles for plant proteases in defence, as well as the regulation and substrates of these enzymes, are waiting to be discovered.


Necroptosis, necrostatins and tissue injury.
Cell death is an integral part of the life of an organism being necessary for the maintenance of organs and tissues. If, however, cell death is allowed to proceed unrestricted, tissue damage and degenerative disease may ensue. Until recently, three morphologically distinct types of cell death were recognized, apoptosis (type I), autophagy (type II) and necrosis (type III). Apoptosis is a highly regulated, genetically determined mechanism designed to dismantle cells systematically (e.g. cells that are no longer functionally viable), via protease (caspase) action, and maintain homeostasis. Autophagy is responsible for the degradation of cytoplasmic material, e.g. proteins and organelles, through autophagosome formation and subsequent proteolytic degradation by lysosomes, and is normally considered in the context of survival although it is sometimes associated with cell death. Necrosis was formerly considered to be an accidental, unregulated form of cell death resulting from excessive stress, although it has been suggested that this is an over-simplistic view as necrosis may under certain circumstances involve the mobilization of specific transduction mechanisms. Indeed, recently, an alternative death pathway, termed necroptosis, was delineated and proposed as a form of 'programmed necrosis'. Identified with the aid of specific inhibitors called necrostatins, necroptosis shares characteristics with both necrosis and apoptosis. Necroptosis involves Fas/tumour necrosis factor-α death domain receptor activation and inhibition of receptor-interacting protein I kinase, and it has been suggested that it may contribute to the development of neurological and myocardial diseases. Significantly, necrostatin-like drugs have been mooted as possible future therapeutic agents for the treatment of degenerative conditions.


Polyphyly of Asian Tree Toads, Genus Pedostibes Günther, 1876 (Anura: Bufonidae), and the Description of a New Genus from Southeast Asia.
The Asian Tree Toad genus Pedostibes, as currently understood, exhibits a conspicuously disjunct distribution, posing several immediate questions relating to the biogeography and taxonomy of this poorly known group. The type species, P. tuberculosus and P. kempi, are known only from India, whereas P. hosii, P. rugosus, and P. everetti are restricted to Southeast Asia. Several studies have shown that these allopatric groups are polyphyletic, with the Indian Pedostibes embedded within a primarily South Asian clade of toads, containing the genera Adenomus, Xanthophryne, and Duttaphrynus. Southeast Asian Pedostibes on the other hand, are nested within a Southeast Asian clade, which is the sister lineage to the Southeast Asian river toad genus Phrynoidis. We demonstrate that Indian and Southeast Asian Pedostibes are not only allopatric and polyphyletic, but also exhibit significant differences in morphology and reproductive mode, indicating that the Southeast Asian species' are not congeneric with the true Pedostibes of India. As a taxonomic solution, we describe a new genus, Rentapia gen. nov. to accommodate the Southeast Asian species.


Successful integration of hepatitis C evaluation and treatment services with methadone maintenance.
Despite high rates of hepatitis C virus (HCV) infection, relatively few current or former injection drug users receive evaluation and treatment for HCV. Here, we demonstrate the feasibility and effectiveness of integrating HCV care and methadone maintenance treatment (MMT). We hypothesized that colocation of these services would result in improved access to and utilization of HCV care. In this retrospective observational study, all patient charts from a single MMT clinic were reviewed 2 years after HCV care and MMT were integrated. Information obtained included screening for and counseling about HCV infection status, on-site HCV treatment and outcomes, and demographic and substance abuse data. Two hundred ninety-one patient charts were reviewed. Two hundred eighty-one (99%) patients were screened for HCV antibody (HCV-Ab), and 188 (65%) were positive. Forty-nine (17%) patients were HIV/HCV coinfected. Ninety-eight percent of the HCV-Ab-positive patients received HCV counseling. Hundred fifty-nine (85%) of the HCV-Ab-positive patients were eligible to receive further evaluation and treatment for HCV on site, and 125 (78%) accepted. Hundred eighteen (94%) patients were tested for chronic HCV, and 83 were determined to have chronic HCV. Twenty-five patients received liver biopsy; low-stage disease was found in 7 patients. Twenty-one patients initiated HCV treatment. Sustained viral response was achieved in 8 patients. Seventeen patients had contraindications to HCV treatment. Further workup was prevented or delayed in 45 patients for various reasons, most commonly due to personal choice (29 patients). This study demonstrates that current and former injection drug users can be engaged successfully in evaluation and treatment of HCV infection when these services are collocated with MMT.


Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic.
This study aimed to determine the impact of pulmonary complications on death after surgery both before and during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This was a patient-level, comparative analysis of two, international prospective cohort studies: one before the pandemic (January-October 2019) and the second during the SARS-CoV-2 pandemic (local emergence of COVID-19 up to 19 April 2020). Both included patients undergoing elective resection of an intra-abdominal cancer with curative intent across five surgical oncology disciplines. Patient selection and rates of 30-day postoperative pulmonary complications were compared. The primary outcome was 30-day postoperative mortality. Mediation analysis using a natural-effects model was used to estimate the proportion of deaths during the pandemic attributable to SARS-CoV-2 infection. This study included 7402 patients from 50 countries; 3031 (40.9 per cent) underwent surgery before and 4371 (59.1 per cent) during the pandemic. Overall, 4.3 per cent (187 of 4371) developed postoperative SARS-CoV-2 in the pandemic cohort. The pulmonary complication rate was similar (7.1 per cent (216 of 3031) versus 6.3 per cent (274 of 4371); P = 0.158) but the mortality rate was significantly higher (0.7 per cent (20 of 3031) versus 2.0 per cent (87 of 4371); P < 0.001) among patients who had surgery during the pandemic. The adjusted odds of death were higher during than before the pandemic (odds ratio (OR) 2.72, 95 per cent c.i. 1.58 to 4.67; P < 0.001). In mediation analysis, 54.8 per cent of excess postoperative deaths during the pandemic were estimated to be attributable to SARS-CoV-2 (OR 1.73, 1.40 to 2.13; P < 0.001). Although providers may have selected patients with a lower risk profile for surgery during the pandemic, this did not mitigate the likelihood of death through SARS-CoV-2 infection. Care providers must act urgently to protect surgical patients from SARS-CoV-2 infection.


Dual Processing Model for Medical Decision-Making: An Extension to Diagnostic Testing.
Dual Processing Theories (DPT) assume that human cognition is governed by two distinct types of processes typically referred to as type 1 (intuitive) and type 2 (deliberative). Based on DPT we have derived a Dual Processing Model (DPM) to describe and explain therapeutic medical decision-making. The DPM model indicates that doctors decide to treat when treatment benefits outweigh its harms, which occurs when the probability of the disease is greater than the so called "threshold probability" at which treatment benefits are equal to treatment harms. Here we extend our work to include a wider class of decision problems that involve diagnostic testing. We illustrate applicability of the proposed model in a typical clinical scenario considering the management of a patient with prostate cancer. To that end, we calculate and compare two types of decision-thresholds: one that adheres to expected utility theory (EUT) and the second according to DPM. Our results showed that the decisions to administer a diagnostic test could be better explained using the DPM threshold. This is because such decisions depend on objective evidence of test/treatment benefits and harms as well as type 1 cognition of benefits and harms, which are not considered under EUT. Given that type 1 processes are unique to each decision-maker, this means that the DPM threshold will vary among different individuals. We also showed that when type 1 processes exclusively dominate decisions, ordering a diagnostic test does not affect a decision; the decision is based on the assessment of benefits and harms of treatment. These findings could explain variations in the treatment and diagnostic patterns documented in today's clinical practice.


Automated diagnosis of autism: in search of a mathematical marker.
Autism is a type of neurodevelopmental disorder affecting the memory, behavior, emotion, learning ability, and communication of an individual. An early detection of the abnormality, due to irregular processing in the brain, can be achieved using electroencephalograms (EEG). The variations in the EEG signals cannot be deciphered by mere visual inspection. Computer-aided diagnostic tools can be used to recognize the subtle and invisible information present in the irregular EEG pattern and diagnose autism. This paper presents a state-of-the-art review of automated EEG-based diagnosis of autism. Various time domain, frequency domain, time-frequency domain, and nonlinear dynamics for the analysis of autistic EEG signals are described briefly. A focus of the review is the use of nonlinear dynamics and chaos theory to discover the mathematical biomarkers for the diagnosis of the autism analogous to biological markers. A combination of the time-frequency and nonlinear dynamic analysis is the most effective approach to characterize the nonstationary and chaotic physiological signals for the automated EEG-based diagnosis of autism spectrum disorder (ASD). The features extracted using these nonlinear methods can be used as mathematical markers to detect the early stage of autism and aid the clinicians in their diagnosis. This will expedite the administration of appropriate therapies to treat the disorder.


Isolated factor V deficiency in a patient with elevated PT and aPTT during routine pre-operative laboratory screening.
Isolated factor V (FV) deficiency is a rare disorder with approximately 150 cases reported in the literature since 1943. Bleeding symptoms from FV deficiency vary widely. FV deficiency usually manifests early in the life. We present a 59-year-old case with FV deficiency discovered during pre-operative laboratory screen.


Environmental noise and incident mental health problems: A prospective cohort study among school children in Germany.
Environmental noise is considered a threat to public health as 20% of the EU population is exposed to health influencing noise levels. An association of noise and mental health problems in children has been suggested by some studies, but results are not consistent and there are no longitudinal studies of this association. Our aim was to investigate the influence of different environmental noise sources at children's homes on incident mental health problems in school-aged children. A cohort study of children from first (t0) to fourth grade (t1) of primary school was conducted. Different environmental noise sources (day/night separately) at children's home were assessed via parental annoyance reports. Increased noise exposure between t0 and t1 was the exposure variable. Incident mental health problems were assessed with the parental version of the Strengths and Difficulties Questionnaire (SDQ). RRs and 95% CIs were analysed to investigate the association between different noise sources and incident mental health problems. The study population consisted of 583 boys and 602 girls. The most common increase in noise exposure between t0 and t1 was road traffic noise day (26.38%). After adjusting for covariates exposure to road traffic night was significantly associated with the total difficulties score (RR=2.06; 95% CI=1.25-3.40), emotional symptoms (RR=1.69, 95% CI=1.04-2.72), and conduct problems (RR=1.57, 95% CI=1.04-2.38). Noise by neighbours during the day was associated with conduct problems (RR=1.62, 95% CI=1.11-2.40) and hyperactivity (RR=1.69, 95% CI=1.08-2.65). Aircraft noise day and construction work day were not associated with any of the SDQ categories at a significant level. Environmental noise is an important public health problem. This is the first study to investigate the association of a broad range of noise sources and incident mental health problems in children in a cohort study. Our results suggest that exposure to noise at children's home is associated with mental health problems such as emotional symptoms, conduct problems and hyperactivity.


Differential light scattering: a physical method for identifying living bacterial cells.
Differential light scattering techniques appear to represent an attractive physical method for the rapid identification of various microorganisms. Certain general results of inverse scattering theory suggest strongly that characteristic of each distinct microorganism that scatters light is an essentially unique scattering pattern, i.e., unique differential scattered intensity and polarization. Although a mathematically rigorous inversion procedure seems impractical at this time, the use of detailed differential scattered intensity data as an identification fingerprint shows considerable. promise. Published measurements on nonbiological scatterers confirm this possibility. A variety of calculations are presented that contrast the expected scattering characteristics of certain microorganisms such as Bacillus subtilis, B. anthracis, Staphylococcus epidermidis, S. aureus, Escherichia coli, and the spores of B. mcgaterium and B. cereus. Experimental and instrumentation difficulties and possible procedures are discussed. A review and laboration of some applicable features of Rayleigh-Gans scattering are included as an appendix.


Results of peripheral laser photocoagulation in pars planitis.
To determine the effect of peripheral retinal laser photocoagulation (PLP) on visual acuity, intraocular inflammation, and other ocular findings, including retinal neovascularization in eyes with pars planitis. A retrospective chart review of eyes with pars planitis that had undergone PLP. Twenty-two eyes in 17 patients with pars planitis had undergone treatment with PLP at 2 centers. The mean age at the time of treatment was 19.3 years. Following treatment, mean follow-up was 16.3 months (range, 6 to 37 months). Mean visual acuity was 20/60 preoperatively and 20/50 postoperatively. This level of improvement was not statistically significant (P > .10), but there was a statistically significant decrease in the use of corticosteroids between the preoperative examination and the last postoperative examination (86% versus 27%, P < .05). There was also a statistically significant decrease in vitritis at the last follow-up (P = .0008) and a decrease in neovascularization of the vitreous base (P = .03) and in clinically apparent cystoid macular edema (P = .02). Epiretinal membranes were noted in 23% of eyes preoperatively and in 45% of eyes postoperatively. Only one of these epiretinal membranes was considered to be visually significant. One eye developed a tonic dilated pupil, which slowly improved. Although the long-term natural history of clinical findings in pars planitis is not well documented, PLP appears to decrease the need for corticosteroids while stabilizing visual acuity. It also appears to decrease vitreous inflammation. PLP has few complications and should be considered in patients with pars planitis who are unresponsive or have adverse reactions to corticosteroids.


Barriers to immunisation in general practice.
To identify barriers to immunisation in general practice. The study was conducted in Perth, Western Australia, as a cross-sectional postal survey between November 1996 and January 1997. Questionnaires were sent to all known GPs in three of the seven metropolitan Divisions of General Practice, of whom 301 (72%) responded. When a child presented with a minor illness and there were no contraindications to immunisation, 62% of GPs said they would always or frequently offer immunisation. Immunisation would be withheld incorrectly because of an upper respiratory tract infection by 43% of GPs and because of antibiotics by 50%. Combined diphtheria-tetanus vaccine (CDT) would be substituted incorrectly for diphtheria-tetanus-pertussis vaccine (DTP) by 41% if there was an unexplained temperature of 38 degrees C following a previous dose of DTP. While more than half (56%) reported that vaccines were correctly stored, only 26% reported that the refrigerator temperature was checked daily. Eighty per cent reported that they completed an Australian Childhood Immunisation Register notification form. GPs require ongoing education about contra-indications to immunisation and when substitution of CDT for DTP is required. There is room for increased opportunistic immunisation and encouragement to notify the Australian Childhood Immunisation Register when they immunise a child. A major challenge is to find an innovative approach that would encourage and enable GPs to assess immunisation status and offer immunisation where appropriate at every clinical encounter.


The long-term impact of post traumatic stress disorder on recovery from heroin dependence.
The high prevalence of post traumatic stress disorder (PTSD) among people with heroin dependence and its impact on short term outcomes has been well established. The impact of PTSD on long-term recovery is, however, unknown. This paper examines the impact of current and lifetime PTSD on long-term recovery from heroin dependence among participants who took part in the 11-year follow-up of the Australian Treatment Outcome Study (ATOS), a prospective naturalistic longitudinal study of 615 people with heroin dependence recruited from Sydney, Australia, in 2001-2002. Seventy-one percent of the cohort (n = 431) were re-interviewed 11-years post study entry. Outcomes examined included heroin and other drug use, dependence, general physical and mental health, depression, PTSD, employment, and the incidence of trauma exposure, overdose, imprisonment, and attempted suicide over the 11- year follow-up. Despite having a poorer profile at baseline, individuals with current PTSD or a history of PTSD at baseline demonstrated similar levels of improvement to those without a history of PTSD in all outcome domains across the 11-year follow-up, PTSD was associated with consistently higher levels of major depression, and attempted suicide, subsequent trauma exposure, and poorer occupational functioning across the 11-year follow-up. These findings highlight the importance of interventions aimed at occupational rehabilitation, reducing the likelihood of retraumatisation, and addressing PTSD and associated comorbidities among people with heroin dependence.


Characteristics of arterial plasma membrane in renovascular hypertension in rats.
Protein content, enzymatic activites and Ca2+ accumulation capacities were studied in plasma membrane fractions isolated from mesenteric arteries of rats made hypertensive by renal artery stenosis with and without contralateral nephrectomy, i.e., one-kidney, one clip (1-KHR) and two-kidney, one clip (2-KHR) hypertension, respectively. Both types of renovascular hypertension showed similar vascular plasma membrane abnormalities which included increased total protein contents, enhanced alkaline phosphatase activities and reduced ATP-dependent Ca2+ accumulation compared to control values. The altered alkaline phosphatase activity and ATP-dependent Ca2+ accumulation appeared to be associated with blood pressure elevation in both types of hypertension and may be related to the elevation of blood pressure insensitive to captopril (SQ 14,225) in 1-KHR and 2-KHR. These results are consistent with the current concept of biochemical abnormalities of arterial smooth muscle in the development ostem.


Mechanism of replication-coupled DNA interstrand crosslink repair.
DNA interstrand crosslinks (ICLs) are toxic DNA lesions whose repair occurs in the S phase of metazoans via an unknown mechanism. Here, we describe a cell-free system based on Xenopus egg extracts that supports ICL repair. During DNA replication of a plasmid containing a site-specific ICL, two replication forks converge on the crosslink. Subsequent lesion bypass involves advance of a nascent leading strand to within one nucleotide of the ICL, followed by incisions, translesion DNA synthesis, and extension of the nascent strand beyond the lesion. Immunodepletion experiments suggest that extension requires DNA polymerase zeta. Ultimately, a significant portion of the input DNA is fully repaired, but not if DNA replication is blocked. Our experiments establish a mechanism for ICL repair that reveals how this process is coupled to DNA replication.


Altered expression of the alpha7beta1 integrin in human and murine muscular dystrophies.
The alpha7beta1 integrin is the primary laminin receptor on skeletal myoblasts and adult myofibers. It has distinct functions during muscle development and contributes to muscle structural integrity. We have studied this integrin in cases where expression of dystrophin or laminin are compromised. Immunofluorescence demonstrates an increase in alpha7beta1 in patients with Duchenne muscular dystrophy and in mdx mice that lack dystrophin. Analysis of RNA from mdx mice and from patients with Duchenne and Becker muscular dystrophies indicates that the increase in the alpha7beta1 integrin is regulated at the level of alpha7 gene transcription. In contrast, the levels of alpha7beta1 integrin are severely diminished in patients with laminin alpha2 chain congenital dystrophy muscular dystrophy and in dy/dy mice that also do not make the alpha2 laminin chain. Analysis of RNA from the hindlimbs of dy/dy mice demonstrated that in the absence of laminin alpha7 gene transcription is inhibited and limited to specific alternatively spliced isoforms. We suggest that the increased expression of alpha7beta1 integrin in the absence of dystrophin compensates for the reduced dystrophin-mediated linkage of fibers with the basal lamina and modulates the development of pathology associated with these diseases. The decrease in alpha7beta1 integrin and its transcripts in the absence of laminin likely contributes to the severe myopathy that results from laminin alpha2 chain deficiency and suggests that laminin-2 regulates expression of the alpha7 integrin gene. The role of the alpha7beta1 integrin in muscle integrity also suggests that compromised expression of this receptor may underlie as yet undefined myopathies.


Sodium bisulfate and a sodium bisulfate/tannin mixture decreases pH when added to an in vitro incubated poultry cecal or fecal contents while reducing Salmonella Typhimurium marker strain survival and altering the microbiome.
The objective of the present study was to investigate the ability of animal feed-grade sodium bisulfate (SBS) and a mixture of sodium bisulfate/tannin to inhibit the growth of Salmonella using an anerobic in vitro mixed cecal culture to mimic the conditions within the chicken cecum. An initial inoculum of Salmonella Typhimurium was introduced to an anerobic dilution solution containing 1/3000 diluted cecal bacteria and solids consisting of ground chicken feed and different percentages of solid SBS or SBS/tannin, and surviving organisms were enumerated. Two different experimental designs were employed. In the "unadapted" treatment, the S. Typhimurium was added at the beginning of the culture incubation along with cecal bacteria and chicken feed/SBS or chicken feed/SBS/tannin. In the "adapted" treatment, S. Typhimurium was added after a 24 hour pre-incubation of the cecal bacteria with the chicken feed/SBS or chicken feed/SBS/tannin. Adding SBS resulted in reduction of pH in the cultures which paralleled with the reduction of S. Typhimurium. The SBS alone was found to be inhibitory to S. Typhimurium in the adapted treatment at all concentrations tested (0.25, 0.5, and 0.75%), and the degree of inhibition was concentration-dependent. Salmonella Typhimurium was completely killed in the adapted culture with 0.5% SBS after 24 and 48 h. The SBS/tannin mixture was less inhibitory than SBS alone at the same concentrations in side-by-side comparisons. Testing at a 0.5% SBS concentration, chicken age had little or no effect on log reduction of S. Typhimurium relative to age-matched control cultures without SBS, but age did affect the absolute number of S. Typhimurium surviving, with the greatest decreases occurring at 2 and 4 weeks of age (approx. 103 S. Typhimurium surviving) compared to 6 weeks of age (approx. 105 Salmonella surviving). Microbiome analysis with an Illumina MiSeq platform was conducted to investigate bacterial compositional changes related to the addition of SBS. The relative abundance of Firmicutes (at the phylum level) was decreased, and genera Lactobacillus and Faecalibacterium were increased when SBS was added to the anaerobic mixed culture containing either fecal or cecal material. The antimicrobial action of feed-grade SBS may represent a potential pre-harvest control measure for Salmonella in poultry production.


Influence of changing various parameters in miniscrew-assisted rapid palatal expansion: A three-dimensional finite element analysis.
This study aimed to analyze the effect of changing various parameters of the bone-borne rapid palatal expander (RPE) using the finite element method (FEM). In eight experimental groups, we investigated the effect of the number, position, and length of miniscrews; positional changes of the expander; and changes in the hook length on maxillary expansion. In finite element analysis, we compared the magnitude and distribution of stress, and the displacement changes following expansion of the bone-borne RPE. When we compared the number and position of miniscrews, placing miniscrews in the anterior and posterior sides was advantageous for maxillary expansion in terms of stress distribution and displacement changes. Miniscrew length did not significantly affect stress distribution and displacement changes. Furthermore, anteroposterior displacement of the expander did not significantly affect transverse maxillary expansion but had various effects on vertical changes of the maxilla. The maxilla rotated clockwise when the miniscrews were placed in the anterior region. The hook length of the expander did not show consistent results in terms of changes in stress distribution and magnitude or in displacement changes. The findings of this study suggest that changes in the location and length of the miniscrews and displacement of the bone-borne RPE could affect the pattern of the maxillary expansion, depending on the combination of these factors.


The meaning of 'fruits' and 'vegetables'.
Fruit and vegetable consumption is a focus of research and nutrition education; yet, there is no universal agreement on the meaning of 'fruits' and 'vegetables'. Our objective was to describe survey respondent perceptions about a set of foods with regard to whether the food is a fruit, vegetable or something else. Three cross-sectional studies. Two small studies involving cognitive interviewing sessions; and one large self-administered population survey. US adults in two small studies (n 55 and 80) and one large survey (n 3312), all with multiple race/ethnicities. Perceptions varied. In the survey, rice was considered a vegetable by about 20 % of respondents. In one small study, Spanish speakers were more likely to consider rice a vegetable, and Chinese speakers less likely, than were English speakers. Black beans were frequently classified as something other than vegetable or fruit. Among Hispanics, Spanish speakers were less likely than English speakers to consider beans a vegetable. Overall, tomatoes were classified as both fruit and vegetable, and these perceptions varied by race/ethnicity. Substantial disagreement among the fruit, vegetable and other food domains highlights the importance of clearly defining the desired constructs. Foods that require specific instruction include rice, dried beans, potatoes, tomatoes and fruits and vegetables in mixtures and condiments. For measurement, additional questions or explanations may be needed to clarify which foods are of interest. For communication, the global message to increase consumption of fruit and vegetables should be reinforced with specific guidance.


Genetic movement disorders in patients of Jewish ancestry.
Genetic diseases often cluster in different ethnic groups and may present with recognizable unique clinical manifestations. To summarize current knowledge about movement disorders overrepresented among patients of Jewish ancestry. We searched PubMed and the OMIM and Israeli National Genetic Databases for articles published from 1969 through March 31, 2014, using the search terms Parkinson's disease,movement disorders, ataxia, dystonia, chorea, and Creutzfeldt-Jakob with and Jewish. The final reference list was generated by giving priority to articles directly related to the topic, articles with the latest information, and comprehensive but relevant reviews. About one-third of patients with sporadic Parkinson disease (PD) and more than 40% of patients with familial PD of Ashkenazi Jewish descent likely carry the G2019S mutation in the LRRK2 gene, a mutation in the glucocerebrosidase (GBA) gene, or both. This finding contrasts with only a 10% frequency of these mutations in patients with PD who are of non-Jewish ancestry. A dystonia due to a TOR1A gene mutation is responsible for most early-onset autosomal dominant dystonia, and 90% of Ashkenazi Jews who develop early-onset disease have TOR1A-related dystonia. Familial Creutzfeldt-Jakob disease and cerebrotendinous xanthomatosis tend to cluster among Jews of North African descent, and Machado-Joseph disease is particularly frequent in Yemenite Jews. Genetic forms of PD are much more common in patients of Ashkenazi Jewish ancestry with sporadic and familial PD than in the non-Jewish population. The recognition of the particular movement disorder phenotype, coupled with information about the ethnic origin of the patients, may point to specific genetic testing and lead to early and correct diagnosis.


In defense of representation.
The computational paradigm, which has dominated psychology and artificial intelligence since the cognitive revolution, has been a source of intense debate. Recently, several cognitive scientists have argued against this paradigm, not by objecting to computation, but rather by objecting to the notion of representation. Our analysis of these objections reveals that it is not the notion of representation per se that is causing the problem, but rather specific properties of representations as they are used in various psychological theories. Our analysis suggests that all theorists accept the idea that cognitive processing involves internal information-carrying states that mediate cognitive processing. These mediating states are a superordinate category of representations. We discuss five properties that can be added to mediating states and examine their importance in various cognitive models. Finally, three methodological lessons are drawn from our analysis and discussion.


The nutritional quality of foods carrying health-related claims in Germany, The Netherlands, Spain, Slovenia and the United Kingdom.
Backgroung/Objectives:Compares the nutritional quality of pre-packaged foods carrying health-related claims with foods that do not carry health-related claims. Cross-sectional survey of pre-packaged foods available in Germany, The Netherlands, Spain, Slovenia and the United Kingdom in 2013. A total of 2034 foods were randomly sampled from three food store types (a supermarket, a neighbourhood store and a discounter). Nutritional information was taken from nutrient declarations present on food labels and assessed through a comparison of mean levels, regression analyses and the application of a nutrient profile model currently used to regulate health claims in Australia and New Zealand (Food Standards Australia New Zealand's Nutrient Profiling Scoring Criterion, FSANZ NPSC). Foods carrying health claims had, on average, lower levels, per 100 g, of the following nutrients, energy-29.3 kcal (P<0.05), protein-1.2 g (P<0.01), total sugars-3.1 g (P<0.05), saturated fat-2.4 g (P<0.001), and sodium-842 mg (P<0.001), and higher levels of fibre-0.8 g (P<0.001). A similar pattern was observed for foods carrying nutrition claims. Forty-three percent (confidence interval (CI) 41%, 45%) of foods passed the FSANZ NPSC, with foods carrying health claims more likely to pass (70%, CI 64%, 76%) than foods carrying nutrition claims (61%, CI 57%, 66%) or foods that did not carry either type of claim (36%, CI 34%, 38%). Foods carrying health-related claims have marginally better nutrition profiles than those that do not carry claims; these differences would be increased if the FSANZ NPSC was used to regulate health-related claims. It is unclear whether these relatively small differences have significant impacts on health.


Myoclonic seizure due to cyclopentolate eye drop in a preterm infant.
Cyclopentolate is widely used in ophthalmology for its intense mydriatic and cycloplegic activity. Systemic side effects have been described in both adults and children. Myoclonic seizure is a rare side effect of eye drops that are used in eye examinations. We report herein a case of convulsion in a three month- old girl following cyclopentolate hydrochloride and phenylephrine hydrochloride eye drops, which were used in advance of ophthalmoscopy for examination of retinopathy of prematurity (ROP). Physicians should be aware of the uncommon systemic side effects of cyclopentolate, and drops should be used in appropriate dosages.


The Role of Movement Analysis in Diagnosing and Monitoring Neurodegenerative Conditions: Insights from Gait and Postural Control.
Quantifying gait and postural control adds valuable information that aids in understanding neurological conditions where motor symptoms predominate and cause considerable functional impairment. Disease-specific clinical scales exist; however, they are often susceptible to subjectivity, and can lack sensitivity when identifying subtle gait and postural impairments in prodromal cohorts and longitudinally to document disease progression. Numerous devices are available to objectively quantify a range of measurement outcomes pertaining to gait and postural control; however, efforts are required to standardise and harmonise approaches that are specific to the neurological condition and clinical assessment. Tools are urgently needed that address a number of unmet needs in neurological practice. Namely, these include timely and accurate diagnosis; disease stratification; risk prediction; tracking disease progression; and decision making for intervention optimisation and maximising therapeutic response (such as medication selection, disease staging, and targeted support). Using some recent examples of research across a range of relevant neurological conditions-including Parkinson's disease, ataxia, and dementia-we will illustrate evidence that supports progress against these unmet clinical needs. We summarise the novel 'big data' approaches that utilise data mining and machine learning techniques to improve disease classification and risk prediction, and conclude with recommendations for future direction.


Causal inference when counterfactuals depend on the proportion of all subjects exposed.
The assumption that no subject's exposure affects another subject's outcome, known as the no-interference assumption, has long held a foundational position in the study of causal inference. However, this assumption may be violated in many settings, and in recent years has been relaxed considerably. Often this has been achieved with either the aid of a known underlying network, or the assumption that the population can be partitioned into separate groups, between which there is no interference, and within which each subject's outcome may be affected by all the other subjects in the group via the proportion exposed (the stratified interference assumption). In this article, we instead consider a complete interference setting, in which each subject affects every other subject's outcome. In particular, we make the stratified interference assumption for a single group consisting of the entire sample. We show that a targeted maximum likelihood estimator for the i.i.d. setting can be used to estimate a class of causal parameters that includes direct effects and overall effects under certain interventions. This estimator remains doubly-robust, semiparametric efficient, and continues to allow for incorporation of machine learning under our model. We conduct a simulation study, and present results from a data application where we study the effect of a nurse-based triage system on the outcomes of patients receiving HIV care in Kenyan health clinics.


Chromosome imbalance, normal phenotype, and imprinting.
A duplication of the sub-bands 1q42.11 and 1q42.12 was found in a boy and his mother. The proband has short stature (around the 10th centile) but a normal phenotype and psychomotor development. His mother is also asymptomatic. We found 30 published cases of normal subjects with an imbalance of autosomal euchromatic material. In these cases the imbalance involved either only one G positive band or a G positive and a G negative band. Thus the absence of a phenotypic effect cannot always be ascribed to the deficiency in the G positive bands of coding DNA. Moreover, in some cases, the method of transmission of the chromosome abnormality was such that an imprinting effect could be postulated.


Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.
Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+) T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1-seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive patients with associated CD8(+) T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.


The circular-polarization phase-meter.
A new method to measure the carrier-envelope phase (CEP) of a strong few-cycle laser pulse is introduced. The new concept relies on above threshold ionization (ATI) in circularly polarized laser fields and allows for CEP tagging every single laser pulse generated in few-cycle laser systems at multi-kHz repetition rates. The implementation of the new method is described and discussed quantitatively. It is shown that the introduced circular-polarization phase-meter may offer a series of advantages over existing CEP-tagging schemes based on ATI in linearly polarized laser fields.


Evidence that Nitric Oxide Is Critical for LH Surge Generation in Female Sheep.
Elevated and sustained estradiol concentrations cause a gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) surge that is necessary for ovulation. In sheep, several different neural systems have been implicated in this stimulatory action of estradiol and this study focused on somatostatin (SST) neurons in the ventral lateral region of the ventral medial nucleus (vlVMN) which express c-Fos during the surge. First, we determined if increased activity of SST neurons could be related to elevated GnRH secretion by assessing SST synapses onto GnRH neurons and neurons coexpressing kisspeptin, neurokinin B, dynorphin (KNDy). We found that the percentage of preoptic area GnRH neurons that receive SST input increased during the surge compared with other phases of the cycle. However, since SST is generally inhibitory, and pharmacological manipulation of SST signaling did not alter the LH surge in sheep, we hypothesized that nitric oxide (NO) was also produced by these neurons to account for their activation during the surge. In support of this hypothesis we found that (1) the majority of SST cells in the vlVMN (>80%) contained neuronal nitric oxide synthase (nNOS); (2) the expression of c-Fos in dual-labeled SST-nNOS cells, but not in single-labeled cells, increased during the surge compared with other phases of the cycle; and (3) intracerebroventricular (ICV) infusion of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester, completely blocked the estrogen-induced LH surge. These data support the hypothesis that the population of SST-nNOS cells in the vlVMN are a source of NO that is critical for the LH surge, and we propose that they are an important site of estradiol positive feedback in sheep.


Water relations and growth of three grasses during wet and drought years in a tallgrass prairie.
The water relations and growth of three tallgrass prairie species Panicum virgatum, Andropogon gerardii and A. scoparius were examined in irrigated and unwatered prairie in eastern Kansas (USA). Measurements of the osmotic potential at full turgor, ψ π100 , at zero turgor, ψ0, and growth of vegetative and reproductive tillers were made in a year with above-normal precipitation and a drought year to evaluate: 1) the ability of these grasses to osmotically adjust in response to water stress and 2) the effect of drought or supplemental water on growth of these species. Although these grasses adjusted osmotically even in the wet year, the degree of adjustment of ψ π100 and ψ0 in the drought year was relatively large (0.60-0.78 MPa and 0.88-1.34 MPa, respectively) compared to reports for other species. Seasonal minimum values of ψ π100 and ψ0 for these grasses in the drought year were lower than in most mesic species and seasonal fluctuations in ψ π100 and ψ0 were greater than reported for most mesic or xeric species. The relatively frequent occurrence of drought in sub-humid tallgrass prairies may partially explain the greater than expected magnitude of osmotic adjustment in these grasses.Irrigation in the wet year increased reproductive biomass in the mesic grass P. virgatum, but had no effect on A. gerardii or the more xeric grass A. scoparius. However, irrigation in the drought year increased maximum shoot biomass in all three grasses significantly with the largest increase in P. virgatum. Reproduction in P. virgatum was also increased more by irrigation in the drought year compared to the other grasses. Irrigation did not increase season's end production of A. gerardii in the wet year, but in the drought year production was 28% greater in irrigated than unwatered prairie. The combination of these water relations and growth responses of the three grasses to wetter than normal and drought years supports their reported distribution along a moisture gradient in tallgrass prairies.


The physiology of bcl-2 expression in murine B lymphocytes.
Quantitation of bcl-2 gene expression in B-lineage lymphocytes from normal adult mice allows the identification of four cell populations, characterized by successive three- to fivefold increases in average mRNA levels: bone marrow pre-B cells, bone marrow B cells, splenic B cells and long-lived splenic B cells. Thus, in line with previous experiments using overexpression systems, a correlation between longevity and levels of bcl-2 mRNA exists also in the physiology of B-lineage cells. The data are compatible with a quantitative regulation of expression, possibly determined at selective differentiation steps. No difference in bcl-2 expression was detected by comparing splenic IgD+ with IgD- B cells, while distinctly low levels of bcl-2 mRNA were scored in peritoneal CD5+ and CD5- B cells. These observations indicate that the reported persistence of peritoneal B cells may be controlled by mechanisms other than bcl-2 gene expression.


The effects of experimental conditions of fluorescence quenching on the binding parameters of apigenin to bovine serum albumin by response surface methods.
A fluorescence quenching technique is often used to study interactions between small molecules and serum albumin. However, the results are quite different by using spectroscopic techniques on the same drug-protein interaction research and they may be affected by different conditions (e.g. working solution of pH and ionic strength). In this research, using apigenin as an example, the effect of experimental conditions of fluorescence quenching on the binding parameters of drug to bovine serum albumin was investigated using a response surface method (RSM). The effect of pH, the concentration of NaCl and the concentration Mg(2+) on the quenching constant (KSV), the apparent association constant (Ka) and the number of binding sites (n) was studied by single-factor experiments with pH, [NaCl] and [Mg(2+)] as independent variables and KSV, Ka and n as response values. Prediction models were fit to a quadratic polynomial regression equation and the results showed that both KSV and n displayed a second-order model, whereas Ka displayed linear relation dependence on pH, [NaCl] and [Mg(2+)]. Under these experimental conditions, [NaCl] was the most significant (p < 0.05) impact factor on KSV and Ka, whereas n was most affected by pH (p < 0.05).


Validity and inter-rater reliability of medio-lateral knee motion observed during a single-limb mini squat.
Muscle function may influence the risk of knee injury and outcomes following injury. Clinical tests, such as a single-limb mini squat, resemble conditions of daily life and are easy to administer. Fewer squats per 30 seconds indicate poorer function. However, the quality of movement, such as the medio-lateral knee motion may also be important. The aim was to validate an observational clinical test of assessing the medio-lateral knee motion, using a three-dimensional (3-D) motion analysis system. In addition, the inter-rater reliability was evaluated. Twenty-five (17 women) non-injured participants (mean age 25.6 years, range 18-37) were included. Visual analysis of the medio-lateral knee motion, scored as knee-over-foot or knee-medial-to-foot by two raters, and 3-D kinematic data were collected simultaneously during a single-limb mini squat. Frontal plane 2-D peak tibial, thigh, and knee varus-valgus angles, and 3-D peak hip internal-external rotation, and knee varus-valgus angles were calculated. Ten subjects were scored as having a knee-medial-to-foot position and 15 subjects a knee-over-foot position assessed by visual inspection. In 2-D, the peak tibial angle (mean 89.0 (SE 0.7) vs mean 86.3 (SE 0.4) degrees, p = 0.001) and peak thigh angle (mean 77.4 (SE 1.0) vs mean 81.2 (SE 0.5) degrees, p = 0.001) with respect to the horizontal, indicated that the knee was more medially placed than the ankle and thigh, respectively. Thus, the knee was in more valgus (mean 11.6 (SE 1.5) vs 5.0 (SE 0.8) degrees, p < 0.001) in subjects with the knee-medial-to-foot than in those with a knee-over-foot position. In 3-D, the hip was more internally rotated in those with a knee-medial-to-foot than in those with a knee-over-foot position (mean 10.6 (SE 2.1) vs 4.8 (SE 1.8) degrees, p = 0.049), but there was no difference in knee valgus (mean 6.1 (SE 1.8) vs mean 5.0 (SE 1.2) degrees, p = 0.589). The kappa value and percent agreement, respectively, was >0.90 and 96 between raters. Medio-lateral motion of the knee can reliably be assessed during a single-leg mini-squat. The test is valid in 2-D, while the actual movement, in 3-D, is mainly exhibited as increased internal hip rotation. The single-limb mini squat is feasible and easy to administer in the clinical setting and in research to address lower extremity movement quality.


Efficient analysis of large-scale genome-wide data with two R packages: bigstatsr and bigsnpr.
Genome-wide datasets produced for association studies have dramatically increased in size over the past few years, with modern datasets commonly including millions of variants measured in dozens of thousands of individuals. This increase in data size is a major challenge severely slowing down genomic analyses, leading to some software becoming obsolete and researchers having limited access to diverse analysis tools. Here we present two R packages, bigstatsr and bigsnpr, allowing for the analysis of large scale genomic data to be performed within R. To address large data size, the packages use memory-mapping for accessing data matrices stored on disk instead of in RAM. To perform data pre-processing and data analysis, the packages integrate most of the tools that are commonly used, either through transparent system calls to existing software, or through updated or improved implementation of existing methods. In particular, the packages implement fast and accurate computations of principal component analysis and association studies, functions to remove single nucleotide polymorphisms in linkage disequilibrium and algorithms to learn polygenic risk scores on millions of single nucleotide polymorphisms. We illustrate applications of the two R packages by analyzing a case-control genomic dataset for celiac disease, performing an association study and computing polygenic risk scores. Finally, we demonstrate the scalability of the R packages by analyzing a simulated genome-wide dataset including 500 000 individuals and 1 million markers on a single desktop computer. https://privefl.github.io/bigstatsr/ and https://privefl.github.io/bigsnpr/. Supplementary data are available at Bioinformatics online.


Neighborhood ethnic diversity and trust: the role of intergroup contact and perceived threat.
This research reported here speaks to a contentious debate concerning the potential negative consequences of diversity for trust. We tested the relationship between neighborhood diversity and out-group, in-group, and neighborhood trust, taking into consideration previously untested indirect effects via intergroup contact and perceived intergroup threat. A large-scale national survey in England sampled White British majority (N = 868) and ethnic minority (N = 798) respondents from neighborhoods of varying degrees of diversity. Multilevel path analyses showed some negative direct effects of diversity for the majority group but also confirmed predictions that diversity was associated indirectly with increased trust via positive contact and lower threat. These indirect effects had positive implications for total effects of diversity, cancelling out most negative direct effects. Our findings have relevance for a growing body of research seeking to disentangle effects of diversity on trust that has so far largely ignored the key role of intergroup contact.


Association of worry about cancer to benefit finding and functioning in long-term cancer survivors.
Worry about cancer recurrence or progression is associated with negative effects of cancer, such as worse physical functioning, but associations with positive changes post-cancer, such as benefit finding, are unknown. We measured the proportion of patients reporting frequent worry about cancer recurrence or progression and examined the association between worry about cancer recurrence or progression to benefit finding and functioning in cancer. We surveyed 594 long-term (5-10 years post-diagnosis) survivors of cancer (breast, prostate, colorectal, lung, melanoma) in this cross-sectional study. The survey asked about worry about cancer recurrence/progression, negative effects of cancer on mental and physical function, and benefit finding as a result of the cancer (positive effects). Multivariate regressions estimated associations of worry about cancer with negative and positive effects of cancer. Worrying about cancer often or all the time was reported by 19.6% of survivors. Worry about cancer was related to worse functioning (odds ratio (OR) range 1.40 to 1.46, all p's < .01). Worry about recurrence/progression was unrelated to benefit finding (all p's > .10). Worry about cancer was associated with negative, but not positive, effects of cancer. Treating worry about cancer is unlikely to reduce benefit finding after cancer. Given the high prevalence of worry about cancer and relationship to negative effects of cancer, clinical care should attempt to address this worry for long-term survivors.


Norepinephrine turnover in the heart and spleen of the cardiomyopathic Syrian hamster.
Although a reduction in myocardial norepinephrine stores in cardiac hypertrophy and congestive failure is well documented, norepinephrine turnover has been inadequately studied in such hearts. We compared norepinephrine turnover in control and cardiomyopathic hamsters by following the decline in specific activity of myocardial norepinephrine after labelling with an intraperitoneal tracer dose of 3H-norepinephrine. Adult myocardial norepinephrine concentrations were not attained until 4 weeks of age in both strains. There was no difference in the rate of constant (K) for myocardial norepinephrine turnover (0.107+/-0.004 hours-1 vs. 0.100+/-0.005 hours-1) in the two strains of hamsters during the neonatal period. In young control hamsters, K fell to 0.064+/-0.004 hours-1, but that for age-matched hamsters with mild cardiac hypertrophy was 0.102+/-0.001 hours-1 (P less than 0.001). There was little change in K as control hamsters aged. With the development of more severe hypertrophy in cardiomyopathic hamsters, cardiac norepinephrine decreased and resting K rapidly increased to approach the value obtained when hamsters were subjected to immobilization stress (0.302+/-0.013 hours-1). The maximum achievable K remained the same for both control and dystrophic hamsters even during terminal disease. Prolonged immobilization led to a reduction in cardiac norepinephrine in both strains. Ganglionic blockade of failing hamsters completely restored the levels of both cardiac norepinephrine and K to control values. Splenic noradrenergic nerves showed no change in K, norepinephrine content, or maximum K during cardiac decompensation. We conclude that, in the late stages of hamster cardiomyopathy, there is a progressive and possibly specific increase in cardiac sympathetic tone which leads to a concomitant decrease in cardiac norepinephrine. With the loss of sympathetic reserve, congestive failure supervenes.


Positive and balancing selection on SLC18A1 gene associated with psychiatric disorders and human-unique personality traits.
Maintenance of genetic variants susceptible to psychiatric disorders is one of the intriguing evolutionary enigmas. The present study detects three psychiatric disorder-relevant genes (CLSTN2, FAT1, and SLC18A1) that have been under positive selection during the human evolution. In particular, SLC18A1 (vesicular monoamine transporter 1; VMAT1) gene has a human-unique variant (rs1390938, Thr136Ile), which is associated with bipolar disorders and/or the anxiety-related personality traits. 136Ile shows relatively high (20-61%) frequency in non-African populations, and Tajima's D reports a significant peak around the Thr136Ile site, suggesting that this polymorphism has been positively maintained by balancing selection in non-African populations. Moreover, Coalescent simulations predict that 136Ile originated around 100,000 years ago, the time being generally associated with the Out-of-Africa migration of modern humans. Our study sheds new light on a gene in monoamine pathway as a strong candidate contributing to human-unique psychological traits.


Echocardiogram-gated computed tomographic and magnetic resonance angiographies for the detection of pulsatile expansion at the intracranial arterial bifurcation.
To identify the pulsatile small vascular lesion by echocardiogram (ECG)-gated computed tomographic (CT) and magnetic resonance (MR) angiographies. Seven patients who exhibited small evagination at the cerebral artery bifurcations on 3-dimensional (3D) time-of-flight MR angiogram were enrolled. They were examined by conventional/ECG-gated CT angiogram (n = 6) and ECG-gated MR angiogram (n = 5). Echocardiogram-gated MR angiogram was performed with 3D time of flight, triggered after each time window. From ECG-gated CT and MR angiograms, consecutive 10-phase images within a single cardiac cycle were obtained. The pulsatile change of evagination was demonstrated on both ECG-gated CT angiogram (5 of 6 patients) and ECG-gated MR angiogram (all 5 patients). Flattening of the evagination during the diastolic phase was observed in 4 of 6 ECG-gated CT angiograms and 3 of 5 ECG-gated MR angiograms. Of note was a patient with a tiny evagination (<2 × 1 mm); pulsatile change was demonstrated only by ECG-gated MR angiogram. The pulsatile expansion of evagination at the cerebral artery bifurcation can be demonstrated on ECG-gated CT/MR angiograms.


Prevalence of type 2 diabetes in Nepal: a systematic review and meta-analysis from 2000 to 2014.
Understanding the prevalence of type 2 diabetes in Nepal can help in planning for health services and recognising risk factors. This review aims to systematically identify and collate studies describing the prevalence of type 2 diabetes, to summarise the findings, and to explore selected factors that may influence prevalence estimates. This systematic review was conducted in adherence to the MOOSE Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies. Medical Literature Analysis and Retrieval System (MEDLINE) database from 1 January 2000 to 31 December 2014 was searched for the prevalence of type 2 diabetes among Nepalese populations with a combination of search terms. We exploded the search terms to include all possible synonyms and spellings obtained in the search strategy. Additionally, we performed a manual search for other articles and references of published articles. We found 65 articles; 10 studies fulfilled the inclusion criteria and were included in the analyses. These 10 studies comprised a total of 30,218 subjects. The sample size ranged from 489 to 14,009. All the studies used participants older than age 15, of whom 41.5% were male and 58.5% female. All the studies were cross-sectional and two were hospital-based. Prevalence of type 2 diabetes ranged from a minimum of 1.4% to a maximum of 19.0% and pooled prevalence of type 2 diabetes was 8.4% (95% CI: 6.2-10.5%). Prevalence of type 2 diabetes in urban and rural populations was 8.1% (95% CI: 7.3-8.9%) and 1.0% (95% CI: 0.7-1.3%), respectively. This is, to our knowledge, the first study to systematically evaluate the literature of prevalence of type 2 diabetes in Nepal. Results showed that type 2 diabetes is currently a high-burden disease in Nepal, suggesting a possible area to deliberately expand preventive interventions as well as efforts to control the disease.


Inhibition of CNS remyelination by the presence of semaphorin 3A.
Failure of oligodendrocyte precursor cell (OPC) differentiation has been recognized as the leading cause for the failure of myelin regeneration in diseases such as multiple sclerosis (MS). One explanation for the failure of OPC differentiation in MS is the presence of inhibitory molecules in demyelinated lesions. So far only a few inhibitory substrates have been identified in MS lesions. Semaphorin 3A (Sema3A), a secreted member of the semaphorin family, can act as repulsive guidance cue for neuronal and glial cells in the CNS. Recent studies suggest that Sema3A is also expressed in active MS lesions. However, the implication of Sema3A expression in MS lesions remains unclear as OPCs are commonly present in chronic demyelinated lesions. In the present study we identify Sema3A as a potent, selective, and reversible inhibitor of OPC differentiation in vitro. Furthermore, we show that administration of Sema3A into demyelinating lesions in the rat CNS results in a failure of remyelination. Our results imply an important role for Sema3A in the differentiation block occurring in MS lesions.


Mitotic chromosome transmission fidelity mutants in Saccharomyces cerevisiae.
We have isolated 136 independent mutations in haploid yeast strains that exhibit decreased chromosome transmission fidelity in mitosis. Eighty-five percent of the mutations are recessive and 15% are partially dominant. Complementation analysis between MATa and MAT alpha isolates identifies 11 chromosome transmission fidelity (CTF) complementation groups, the largest of which is identical to CHL1. For 49 independent mutations, no corresponding allele has been recovered in the opposite mating type. The initial screen monitored the stability of a centromere-linked color marker on a nonessential yeast chromosome fragment; the mitotic inheritance of natural yeast chromosome III is also affected by the ctf mutations. Of the 136 isolates identified, seven were inviable at 37 degrees and five were inviable at 11 degrees. In all cases tested, these temperature conditional lethalities cosegregated with the chromosome instability phenotype. Five additional complementation groups (ctf12 through ctf16) have been defined by complementation analysis of the mutations causing inviability at 37 degrees. Twenty-three of the 136 isolates exhibited growth defects at concentrations of benomyl permissive for the parent strain, and nine appeared to be tolerant of inhibitory levels of benomyl. All of the mutant strains showed normal sensitivity to ultraviolet and gamma-irradiation. Further characterization of these mutant strains will describe the functions of gene products crucial to the successful execution of processes required for aspects of the chromosome cycle that are important for chromosome transmission fidelity in mitosis.


Isolation and characterization of circulating melanoma cells by size filtration and fluorescent in-situ hybridization.
Isolation of circulating tumor cells (CTCs) from blood of melanoma patients has been difficult owing to inconsistent expression of surface antigens. Here we report on the isolation, detection, and characterization of CTCs from blood of melanoma patients using microfiltration and fluorescent in-situ hybridization (FISH). Two tubes of blood from 15 patients with advanced melanoma were collected. These two tubes subsequently underwent filtration through a membrane with pore sizes of 7.5 μm. Isolated cells from one tube were analyzed by FISH for RREB1 (6p24), MYB (6q32), SE6 (D6Z1), and CCND1 (11q13) and the other paired specimen was analyzed by immunofluorescence for HMB45, melanoma-associated antigen recognized by T cells-1, tyrosinase and melanogenesis associated transcription factor. We identified CTCs in 10 out of 13 melanoma samples by immunofluorescence (2.5-99 CTCs/3 ml of blood) and in 13 specimens by FISH (7.2-76 CTCs/3 ml of blood) with more CTCs identified by FISH in 10 out 13 samples. Two filters failed. Our results show that CTCs are detectable in the majority of patients with advanced melanoma. These tools will be useful in characterizing treatment related changes of melanoma in CTCs.


Smooth muscle Notch1 mediates neointimal formation after vascular injury.
Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury. We performed carotid artery ligation in wild-type, control (SMC-specific Cre recombinase transgenic [smCre-Tg]), general Notch1 heterozygous deficient (N1+/-), SMC-specific Notch1 heterozygous deficient (smN1+/-), and general Notch3 homozygous deficient (N3-/-) mice. Compared with wild-type or control mice, N1+/- and smN1+/- mice showed a 70% decrease in neointimal formation after carotid artery ligation. However, neointimal formation was similar between wild-type and N3-/- mice. Indeed, SMCs derived from explanted aortas of either N1(+/-)- or smN1+/- mice showed decreased chemotaxis and proliferation and increased apoptosis compared with control or N3-/- mice. This correlated with decreased staining of proliferating cell nuclear antigen-positive cells and increased staining of cleaved caspase-3 in the intima of N1(+/-)- or smN1+/- mice. In SMCs derived from CHF1/Hey2-/- mice, activation of Notch signaling did not lead to increased SMC proliferation or migration. These findings indicate that Notch1, rather than Notch3, mediates SMC proliferation and neointimal formation after vascular injury through CHF1/Hey2 and suggest that therapies that target Notch1/CHF1/Hey2 in SMCs may be beneficial in preventing vascular proliferative diseases.