Human Immunodeficiency Virus and Risk of Type 2 Diabetes in a Large Adult Cohort in Jos, Nigeria.
Human immunodeficiency virus (HIV) infection and the use of antiretroviral therapy (ART) may increase the risk of type 2 diabetes mellitus (T2DM). However, data from regions with a high burden of HIV/AIDS are limited. We determined the prevalence of T2DM at the time of presentation to a large HIV clinic in Nigeria, as well as the incidence of diabetes 12 months following ART initiation. Data from patients enrolled for ART from 2011 to 2013 was analyzed, including 2632 patients on enrollment and 2452 reevaluated after 12 months of ART commencement. The presence of diabetes, and demographic, clinical, and biochemical data were retrieved from standardized databases. CD4(+), HIV RNA load, and hepatitis C virus status were noted. Bivariate and logistic regressions were used to identify risk factors for T2DM. Baseline T2DM prevalence was 2.3% (95% confidence interval, 1.8%-2.9%); age, but not body mass index (BMI), was a risk factor for diabetes. After 12 months of ART, an additional 5.3% had developed T2DM. Newly developed diabetes was not associated with age, but was associated with BMI. There were no significant associations between prevalent or incident diabetes and CD4(+), viral load, or type of ART. Diabetes is not uncommon in HIV-infected individuals at the time of presentation to HIV services. Patients initiating ART have a high risk of developing diabetes in the first year of ART. Excessive weight gain should be avoided, as incident diabetes was associated with a BMI ≥25.0 kg/m(2).


Stuttering, language, and cognition: a review and a model of stuttering as suprasegmental sentence plan alignment (SPA).
Extant models of stuttering do not account for the emergence of stuttering at the onset of productive language use; the greater incidence of stuttering during spontaneous speech, on complex sentences, and at sentence-initial positions; the greater incidence of stuttering in bilinguals' 2nd language; the apparent deficiency of stutterers in expressive and receptive language skills; the prevalence of spontaneous recovery from stuttering; and the lack of chronic physiological or articulatory deficits in stuttering children's fluent speech. The author presents a model of stuttering as points of suprasegmental sentence plan alignment (SPA). Such alignment processes occur when, due to on-line sentence production processes, SPAs adopted prior to utterance initiation need to be aligned with revised SPAs. This model parsimoniously accounts for the findings reviewed in the article.


Paint it black: Efficacy of increased wind turbine rotor blade visibility to reduce avian fatalities.
As wind energy deployment increases and larger wind-power plants are considered, bird fatalities through collision with moving turbine rotor blades are expected to increase. However, few (cost-) effective deterrent or mitigation measures have so far been developed to reduce the risk of collision. Provision of "passive" visual cues may enhance the visibility of the rotor blades enabling birds to take evasive action in due time. Laboratory experiments have indicated that painting one of three rotor blades black minimizes motion smear (Hodos 2003, Minimization of motion smear: Reducing avian collisions with wind turbines). We tested the hypothesis that painting would increase the visibility of the blades, and that this would reduce fatality rates in situ, at the Smøla wind-power plant in Norway, using a Before-After-Control-Impact approach employing fatality searches. The annual fatality rate was significantly reduced at the turbines with a painted blade by over 70%, relative to the neighboring control (i.e., unpainted) turbines. The treatment had the largest effect on reduction of raptor fatalities; no white-tailed eagle carcasses were recorded after painting. Applying contrast painting to the rotor blades significantly reduced the collision risk for a range of birds. Painting the rotor blades at operational turbines was, however, resource demanding given that they had to be painted while in-place. However, if implemented before construction, this cost will be minimized. It is recommended to repeat this experiment at other sites to ensure that the outcomes are generic at various settings.


Chiropractic care of children with nocturnal enuresis: a prospective outcome study.
Functional nocturnal enuresis is a common problem which causes a great deal of stress to the suffering children and their families. Some chiropractors advocate chiropractic care as a mode of therapy for this complaint. One hundred and seventy-one enuretic children, aged 4 to 15, were treated with chiropractic adjustments, and their number of wet nights was monitored by their parents. The median number of wet nights per week was 7.0 at the onset of the study. After 2 wk without any therapy, the number of wet nights had decreased to 5.6 (p = .01) and by the end of the treatment this figure was 4.0 (p less than .0001). Following the course of treatment, 15.5% of subjects wet a maximum of 2 nights per fortnight, or, where data for the last 2 wk of therapy were unavailable, a maximum of 1 night/wk. This result is less favorable than the therapeutic success of other common types of therapy, which have reported "cure" rates well above 50%. The only variable which predicted treatment outcome was the initial estimate of bed-wetting; the more severe the condition at the onset, the less likely was the child to improve by the end of the study. In the absence of a control group there appears to be no validity in the claim that chiropractic is a treatment of choice for functional nocturnal enuresis.


Administration of monoclonal anti-T cell antibodies retards murine lupus in BXSB mice.
Murine lupus in BXSB mice is associated with B cell hyperactivity, monocyte proliferation, and impaired T cell function. However, the significance of these abnormalities, and the relationship among them, has not been clearly established. To examine the role of T cells in the pathogenesis of autoimmune disease in BXSB mice, we depleted specific T cell subsets from BXSB males by using rat IgG2b monoclonal antibodies (MAb) to either Thy-1.2 (on all T cells) or L3T4 (on "helper/inducer" T cells). A single injection of anti-Thy-1.2 (6 mg i.v.) at age 3 mo produced a sustained 40 to 50% reduction in circulating T cells for 6 mo. Treatment prevented monocytosis, reduced anti-DNA antibody concentration, and retarded renal disease, but it did not prolong life. Repeated injections of rat MAb to Thy-1.2 were precluded by the development of a host immune response to rat immunoglobulin (Ig) that can cause anaphylaxis in BXSB mice. In contrast, rat MAb to L3T4 stimulated little or no immune response to rat Ig. We therefore were able to treat BXSB mice weekly with anti-L3T4 (2 mg i.p.) from age 3 to 12 mo. Treatment reduced circulating L3T4+ cells beneath the level of detection by fluorescence analysis. It also significantly reduced monocytosis, anti-DNA antibody production, renal disease, and mortality. These findings establish that monocytosis and autoimmunity in BXSB mice are promoted by T cells. They extend our previous observation that MAb to L3T4 retard autoimmunity in NZB/NZW F1 mice. Our finding that treatment with MAb to L3T4 is effective in two strains of lupus-prone mice suggests that treatment with MAb to Leu-3/T4, the human homologue for L3T4, may be effective in people with systemic lupus erythematosus.


COVID-19-Associated Mucormycosis (CAM): An Updated Evidence Mapping.
Mucormycosis, a serious and rare fungal infection, has recently been reported in COVID-19 patients worldwide. This study aims to map all the emerging evidence on the COVID-19-associated mucormycosis (CAM) with a special focus on clinical presentation, treatment modalities, and patient outcomes. An extensive literature search was performed in MEDLINE (Ovid), Embase (Ovid), Cochrane COVID-19 Study Register, and WHO COVID-19 database till 9 June 2021. The primary outcome was to summarize the clinical presentation, treatment modalities, and patient outcomes of CAM. Data were summarized using descriptive statistics and presented in tabular form. This evidence mapping was based on a total of 167 CAM patients with a mean age of 51 ± 14.62 years, and 56.28% of them were male. Diabetes mellitus (73.65% (n = 123)), hypertension (22.75% (n = 38)), and renal failure (10.77% (n = 18)) were the most common co-morbidities among CAM patients. The most common symptoms observed in CAM patients were facial pain, ptosis, proptosis, visual acuity, and vision loss. Survival was higher in patients who underwent both medical and surgical management (64.96%). Overall mortality among CAM patients was found to be 38.32%. In conclusion, this study found a high incidence of CAM with a high mortality rate. Optimal glycemic control and early identification of mucormycosis should be the priority to reduce the morbidity and mortality related to CAM.


Correlations of Geometry and Infill Degree of Extrusion Additively Manufactured 316L Stainless Steel Components.
This study focuses on the effect of part geometry and infill degrees on effective mechanical properties of extrusion additively manufactured stainless steel 316L parts produced with BASF's Ultrafuse 316LX filament. Knowledge about correlations between infill degrees, mechanical properties and dimensional deviations are essential to enhance the part performance and further establish efficient methods for the product development for lightweight metal engineering applications. To investigate the effective Young's modulus, yield strength and bending stress, standard testing methods for tensile testing and bending testing were used. For evaluating the dimensional accuracy, the tensile and bending specimens were measured before and after sintering to analyze anisotropic shrinkage effects and dimensional deviations linked to the infill structure. The results showed that dimensions larger than 10 mm have minor geometrical deviations and that the effective Young's modulus varied in the range of 176%. These findings provide a more profound understanding of the process and its capabilities and enhance the product development process for metal extrusion-based additive manufacturing.


Three-dimensional Patterning of Engineered Biofilms with a Do-it-yourself Bioprinter.
Biofilms are aggregates of bacteria embedded in a self-produced spatially-patterned extracellular matrix. Bacteria within a biofilm develop enhanced antibiotic resistance, which poses potential health dangers, but can also be beneficial for environmental applications such as purification of drinking water. The further development of anti-bacterial therapeutics and biofilm-inspired applications will require the development of reproducible, engineerable methods for biofilm creation. Recently, a novel method of biofilm preparation using a modified three-dimensional (3D) printer with a bacterial ink has been developed. This article describes the steps necessary to build this efficient, low-cost 3D bioprinter that offers multiple applications in bacterially-induced materials processing. The protocol begins with an adapted commercial 3D printer in which the extruder has been replaced with a bio-ink dispenser connected to a syringe pump system enabling a controllable, continuous flow of bio-ink. To develop a bio-ink suitable for biofilm printing, engineered Escherichia coli bacteria were suspended in a solution of alginate, so that they solidify in contact with a surface containing calcium. The inclusion of an inducer chemical within the printing substrate drives expression of biofilm proteins within the printed bio-ink. This method enables 3D printing of various spatial patterns composed of discrete layers of printed biofilms. Such spatially-controlled biofilms can serve as model systems and can find applications in multiple fields that have a wide-ranging impact on society, including antibiotic resistance prevention or drinking water purification, among others.


Coronavirus (COVID-19): A Review of Clinical Features, Diagnosis, and Treatment.
Coronavirus (COVID-19) is an enveloped RNA virus that is diversely found in humans and wildlife. A total of six species have been identified to cause disease in humans. They are known to infect the neurological, respiratory, enteric, and hepatic systems. The past few decades have seen endemic outbreaks in the form of Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome related coronavirus (SARS-CoV). Yet again, we see the emergence of another outbreak due to a new strain called the SARS-CoV-2 virus. The most recent outbreak initially presented as pneumonia of unknown etiology in a cluster of patients in Wuhan, China. The epicenter of infection was linked to seafood and exotic animal wholesale markets in the city. SARS-CoV-2 is highly contagious and has resulted in a rapid pandemic of COVID-19. As the number of cases continues to rise, it is clear that these viruses pose a threat to public health. This review will introduce a general overview of coronavirus and describe the clinical features, evaluation, and treatment of COVID-19 patients. It will also provide a means to raise awareness among primary and secondary healthcare providers during the current pandemic. Furthermore, our review focuses on the most up-to-date clinical information for the effective management, prevention, and counseling of patients worldwide.


Measurement of fecal calprotectin improves monitoring and detection of recurrence of Crohn's disease after surgery.
Crohn's disease (CD) usually recurs after intestinal resection; postoperative endoscopic monitoring and tailored treatment can reduce the chance of recurrence. We investigated whether monitoring levels of fecal calprotectin (FC) can substitute for endoscopic analysis of the mucosa. We analyzed data collected from 135 participants in a prospective, randomized, controlled trial, performed at 17 hospitals in Australia and 1 hospital in New Zealand, that assessed the ability of endoscopic evaluations and step-up treatment to prevent CD recurrence after surgery. Levels of FC, serum levels of C-reactive protein (CRP), and Crohn's disease activity index (CDAI) scores were measured before surgery and then at 6, 12, and 18 months after resection of all macroscopic Crohn's disease. Ileocolonoscopies were performed at 6 months after surgery in 90 patients and at 18 months after surgery in all patients. Levels of FC were measured in 319 samples from 135 patients. The median FC level decreased from 1347 μg/g before surgery to 166 μg/g at 6 months after surgery, but was higher in patients with disease recurrence (based on endoscopic analysis; Rutgeerts score, ≥i2) than in patients in remission (275 vs 72 μg/g, respectively; P < .001). Combined 6- and 18-month levels of FC correlated with the presence (r = 0.42; P < .001) and severity (r = 0.44; P < .001) of CD recurrence, but the CRP level and CDAI score did not. Levels of FC greater than 100 μg/g indicated endoscopic recurrence with 89% sensitivity and 58% specificity, and a negative predictive value (NPV) of 91%; this means that colonoscopy could have been avoided in 47% of patients. Six months after surgery, FC levels less than 51 μg/g in patients in endoscopic remission predicted maintenance of remission (NPV, 79%). In patients with endoscopic recurrence at 6 months who stepped-up treatment, FC levels decreased from 324 μg/g at 6 months to 180 μg/g at 12 months and 109 μg/g at 18 months. In this analysis of data from a prospective clinical trial, FC measurement has sufficient sensitivity and NPV values to monitor for CD recurrence after intestinal resection. Its predictive value might be used to identify patients most likely to relapse. After treatment for recurrence, the FC level can be used to monitor response to treatment. It predicts which patients will have disease recurrence with greater accuracy than CRP level or CDAI score.


Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation.
The presence of inflammatory cells and MPO (myeloperoxidase) in the arterial wall after vascular injury could increase neointima formation by modification of phospholipids. The present study investigates how these phospholipids, in particular oxidized and chlorinated species, are altered within injured vessels and how they affect VSMC (vascular smooth muscle cell) remodelling processes. Vascular injury was induced in C57BL/6 mice and high fat-fed ApoE-/- (apolipoprotein E) mice by wire denudation and ligation of the left carotid artery (LCA). Neointimal and medial composition was assessed using immunohistochemistry and ESI-MS. Primary rabbit aortic SMCs (smooth muscle cells) were utilized to examine the effects of modified lipids on VSMC proliferation, viability and migration at a cellular level. Neointimal area, measured as intima-to-media ratio, was significantly larger in wire-injured ApoE-/- mice (3.62±0.49 compared with 0.83±0.25 in C57BL/6 mice, n=3) and there was increased oxidized low-density lipoprotein (oxLDL) infiltration and elevated plasma MPO levels. Relative increases in lysophosphatidylcholines and unsaturated phosphatidylcholines (PCs) were also observed in wire-injured ApoE-/- carotid arteries. Chlorinated lipids had no effect on VSMC proliferation, viability or migration whereas chronic incubation with oxidized phospholipids stimulated proliferation in the presence of fetal calf serum [154.8±14.2% of viable cells at 1 μM PGPC (1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine) compared with control, n=6]. In conclusion, ApoE-/- mice with an inflammatory phenotype develop more neointima in wire-injured arteries and accumulation of oxidized lipids in the vessel wall may propagate this effect.


Multimode interference devices with input-output ports on the sides.
Multimode interference (MMI) devices are useful for power splitting and for the separation or combination of wavelengths or polarizations, usually in integrated optics. Input-output guides connect to the MMI region by ports. In all previously reported MMI devices, the input and output guides connect only to the ends of the MMI region; i.e., they are end ported. What is believed to be a novel arrangement of the input-output ports on MMI devices is described. By placing input-output ports either partially or entirely on the sides of the MMI region (i.e., side porting), a variety of benefits are achieved and a variety of new devices can be made.


Do preventive interventions for children of mentally ill parents work? Results of a systematic review and meta-analysis.
The transgenerational transmission of mental disorders is one of the most significant causes of psychiatric morbidity. Several risk factors for children of parents with mental illness (COPMI) have been identified in numerous studies and meta-analyses. Many interventions have been developed for this high-risk group, but data about their efficacy are heterogeneous. The current meta-analysis reports on 96 articles including 50 independent samples from randomized controlled trials quantifying effects of preventive interventions for COPMI. Random effect models resulted in small, though significant Effect Sizes (ES) for programs enhancing the mother-infant interaction (ES = 0.26) as well as mothers' (ES = 0.33) and children's (ES = 0.31) behavior that proved to be stable over the 12-month follow-up, except for infants' behavior. Interventions for children/adolescents resulted in significant small effects for global psychopathology (ES = 0.13), as well as internalizing symptoms (ES = 0.17), and increased significantly over time, with externalizing symptoms reaching significance in the follow-up assessments as well (ES = 0.17). Interventions addressing parents and children jointly produced overall larger effects. Higher study quality was associated with smaller effects. There is a dearth of high quality studies that effectively reduce the high risk of COPMI for the development of mental disorders.


Citrus nobiletin ameliorates experimental colitis by reducing inflammation and restoring impaired intestinal barrier function.
Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract. Citrus nobiletin can exert robust anti-inflammatory effects in vivo and in vitro. We evaluated the impact of nobiletin on the excessive inflammatory response and impaired barrier function in a rodent colitis model. Colitis was established by infusion with 1 mL 2,4,6-trinitrobenzene sulfonic acid (TNBS) dissolved in ethanol (40% v/v) in rats at a 125 mg/kg dose. Caco-2 cell monolayer exposed to LPSs is used as a culture model for intestinal permeability measurements. Nobiletin decreased rat epithelial proinflammatory cytokines and mediators production. Nobiletin restored impaired barrier function in colitic rats and Caco-2 monolayer. Nobiletin decreased protein expressions of Akt, nuclear factor-kappa B (NF-κB), and myosin light chain kinase (MLCK) isolated from rat intestinal epithelial tissue and Caco-2 cell, respectively. PI3K inhibitor or siRNA targeting of either Akt or NF-κB mitigated the impact of nobiletin on MLCK expression and barrier function in Caco-2 monolayer, respectively. Nobiletin exerted anti-inflammatory effects in TNBS-induced colitis through the downregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expression. Nobiletin restored barrier function, which had been damaged after TNBS administration, through the inhibition of the Akt-NF-κB-MLCK pathway.


Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine.
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated to infections and it has been suggested that vaccination can trigger the disease. However, little is known about the specific association between clinically manifest influenza/influenza vaccine and CFS/ME. As part of a registry surveillance of adverse effects after mass vaccination in Norway during the 2009 influenza A (H1N1) pandemic, we had the opportunity to estimate and contrast the risk of CFS/ME after infection and vaccination. Using the unique personal identification number assigned to everybody who is registered as resident in Norway, we followed the complete Norwegian population as of October 1, 2009, through national registries of vaccination, communicable diseases, primary health, and specialist health care until December 31, 2012. Hazard ratios (HRs) of CFS/ME, as diagnosed in the specialist health care services (diagnostic code G93.3 in the International Classification of Diseases, Version 10), after influenza infection and/or vaccination were estimated using Cox proportional-hazards regression. The incidence rate of CFS/ME was 2.08 per 100,000 person-months at risk. The adjusted HR of CFS/ME after pandemic vaccination was 0.97 (95% confidence interval [CI]: 0.91-1.04), while it was 2.04 (95% CI: 1.78-2.33) after being diagnosed with influenza infection during the peak pandemic period. Pandemic influenza A (H1N1) infection was associated with a more than two-fold increased risk of CFS/ME. We found no indication of increased risk of CFS/ME after vaccination. Our findings are consistent with a model whereby symptomatic infection, rather than antigenic stimulation may trigger CFS/ME.


Social learning and technological evolution during the Clovis colonization of the New World.
A long-standing debate in Pleistocene archaeology concerns the sources of variation in the technology of colonizing hunter-gatherers. One prominent example of this debate is Clovis technology (13,350-12,500 calendar years before present), which represents the earliest widespread and currently recognizable remains of hunter-gatherers in North America. Clovis projectile points appear to have been made the same way regardless of region, but several studies have documented differences in shape that appear to be regional. Two processes have been proposed for shape variation: (1) stochastic mechanisms such as copy error (drift) and (2) Clovis groups adapting their hunting equipment to the characteristics of prey and local habitat. We used statistical analysis of Clovis-point flake-scar pattern and geometric morphometrics to examine whether drift alone could cause significant differences in the technology of Stone Age colonizing hunter-gatherers. Importantly, our analysis was intraregional to rule out a priori environmental adaptation. Our analysis confirmed that the production technique was the same across the sample, but we found significant shape differences in Clovis point populations made from distinct stone outcrops. Given that current archaeological evidence suggests stone outcrops were "hubs" of regional Clovis activity, our dichotomous, intraregional results quantitatively confirm that Clovis foragers engaged in two tiers of social learning. The lower, ancestral tier relates to point production and can be tied to conformist transmission of tool-making processes across the Clovis population. The upper, derived tier relates to point shape, which can be tied to drift that resulted from increased forager interaction at different stone-outcrop hubs and decreased forager interaction among groups using different outcrops. Given that Clovis artifacts represent the earliest widespread and currently recognizable remains of hunter-gatherers in North America, our results suggest that we need to alter our theoretical understanding of how quickly drift can occur within a colonizing population and create differences among socially learned technological characters.


Impaired Hydrogen Sulfide-Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults.
Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10-6-10-1 mol/L) and sodium sulfide (10-5-101 mol/L) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all P<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN adults (P=0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg; P=0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg; P=0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension.


Modeling the Nonlinear Cortical Response in EEG Evoked by Wrist Joint Manipulation.
Joint manipulation elicits a response from the sensors in the periphery which, via the spinal cord, arrives in the cortex. The average evoked cortical response recorded using electroencephalography was shown to be highly nonlinear; a linear model can only explain 10% of the variance of the evoked response, and over 80% of the response is generated by nonlinear behavior. The goal of this paper is to obtain a nonparametric nonlinear dynamic model, which can consistently explain the recorded cortical response requiring little a priori assumptions about model structure. Wrist joint manipulation was applied in ten healthy participants during which their cortical activity was recorded and modeled using a truncated Volterra series. The obtained models could explain 46% of the variance of the evoked cortical response, thereby demonstrating the relevance of nonlinear modeling. The high similarity of the obtained models across participants indicates that the models reveal common characteristics of the underlying system. The models show predominantly high-pass behavior, which suggests that velocity-related information originating from the muscle spindles governs the cortical response. In conclusion, the nonlinear modeling approach using a truncated Volterra series with regularization, provides a quantitative way of investigating the sensorimotor system, offering insight into the underlying physiology.


Effects of a high-sodium/low-potassium diet on renal calcium, magnesium, and phosphate handling.
The distal convoluted tubule (DCT) of the kidney plays an important role in blood pressure regulation by modulating Na+ reabsorption via the Na+-Cl- cotransporter (NCC). A diet containing high salt (NaCl) and low K+ activates NCC, thereby causing Na+ retention and a rise in blood pressure. Since high blood pressure, hypertension, is associated with changes in serum calcium (Ca2+) and magnesium (Mg2+) levels, we hypothesized that dietary Na+ and K+ intake affects Ca2+ and Mg2+ transport in the DCT. Therefore, the present study aimed to investigate the effect of a high-Na+/low-K+ diet on renal Ca2+ and Mg2+ handling. Mice were divided in four groups and fed a normal-Na+/normal-K+, normal-Na+/low-K+, high-Na+/normal-K+, or high-Na+/low-K+ diet for 4 days. Serum and urine were collected for electrolyte and hormone analysis. Gene and protein expression of electrolyte transporters were assessed in kidney and intestine by qPCR and immunoblotting. Whereas Mg2+ homeostasis was not affected, the mice had elevated urinary Ca2+ and phosphate (Pi) excretion upon high Na+ intake, as well as significantly lower serum Ca2+ levels in the high-Na+/low-K+ group. Alterations in the gene and protein expression of players involved in Ca2+ and Pi transport indicate that reabsorption in the proximal tubular and TAL is affected, while inducing a compensatory response in the DCT. These effects may contribute to the negative health impact of a high-salt diet, including kidney stone formation, chronic kidney disease, and loss of bone mineral density.


Suffering and mental health among older people living in nursing homes-a mixed-methods study.
Background. Knowledge about mixed-methods perspectives that examine anxiety, depression, social support, mental health and the phenomenon of suffering among cognitively intact NH residents is scarce. We aimed to explore suffering and mental health among cognitively intact NH residents. Methods. This study used a mixed-methods design to explore different aspects of the same phenomena of interest to gain a more comprehensive understanding. The qualitative core component comprised a qualitative interview from 18 nursing home residents (≥65 years) about experiences related to pain, grief and loss. The supplementary component comprised interview from the same respondents using the SF-36 Health Survey subscales, the Hospital Anxiety and Depression Scale and the Social Provisions Scale. Results. The individual descriptions reveal suffering caused by painful experiences during life. The quantitative results indicated that symptoms of anxiety and depression were related to mental health and symptoms of anxiety were related to bodily pain and emotional role limitations. Attachment and social integration were associated with vitality and social functioning. Discussion. To improve the situation, more attention should be paid to the residents' suffering related to anxiety, depression and psychosocial relations.


Establishing a health demographic surveillance site in Bhaktapur district, Nepal: initial experiences and findings.
A health demographic surveillance system (HDSS) provides longitudinal data regarding health and demography in countries with coverage error and poor quality data on vital registration systems due to lack of public awareness, inadequate legal basis and limited use of data in health planning. The health system in Nepal, a low-income country, does not focus primarily on health registration, and does not conduct regular health data collection. This study aimed to initiate and establish the first HDSS in Nepal. We conducted a baseline survey in Jhaukhel and Duwakot, two villages in Bhaktapur district. The study surveyed 2,712 households comprising a total population of 13,669. The sex ratio in the study area was 101 males per 100 females and the average household size was 5. The crude birth and death rates were 9.7 and 3.9/1,000 population/year, respectively. About 11% of births occurred at home, and we found no mortality in infants and children less than 5 years of age. Various health problems were found commonly and some of them include respiratory problems (41.9%); headache, vertigo and dizziness (16.7%); bone and joint pain (14.4%); gastrointestinal problems (13.9%); heart disease, including hypertension (8.8%); accidents and injuries (2.9%); and diabetes mellitus (2.6%). The prevalence of non-communicable disease (NCD) was 4.3% (95% CI: 3.83; 4.86) among individuals older than 30 years. Age-adjusted odds ratios showed that risk factors, such as sex, ethnic group, occupation and education, associated with NCD. Our baseline survey demonstrated that it is possible to collect accurate and reliable data in a village setting in Nepal, and this study successfully established an HDSS site. We determined that both maternal and child health are better in the surveillance site compared to the entire country. Risk factors associated with NCDs dominated morbidity and mortality patterns.


Planar integrated wavelength-drop device based on pedestal antiresonant reflecting waveguides and high-Q silica microspheres.
Whispering-gallery modes in silica microspheres can be accessed very efficiently with the recently introduced stripline pedestal antiresonant reflecting optical waveguide (SPARROW) structure. This integrated-optics coupling technique creates novel application opportunities for the high-Q spherical cavities. We report the demonstration of a narrow-band wavelength-drop configuration utilizing SPARROW waveguides and a silica microsphere.


A diet-induced developmental polymorphism in a caterpillar.
Caterpillars of the spring brood of Nemoria arizonaria develop into mimics of the oak catkins upon which they feed. Caterpillars from the summer brood emerge after the catkins have fallen and they develop instead into mimics of oak twigs. This developmental polymorphism may be triggered by the concentration of defensive secondary compounds in the larval diet: all caterpillars raised on catkins, which are low in tannin, developed into catkin morphs; those raised on leaves, which are high in tannin, developed into twig morphs; most raised on artificial diets of catkins with elevated tannin concentrations developed into twig morphs.


Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system.
Transposons have provided important genetic tools for functional genomic screens in lower eukaryotes but have proven less useful in higher eukaryotes because of their low transposition frequency. Here we show that Sleeping Beauty (SB), a member of the Tc1/mariner class of transposons, can be mobilized in mouse somatic cells at frequencies high enough to induce embryonic death and cancer in wild-type mice. Tumours are aggressive, with some animals developing two or even three different types of cancer within a few months of birth. The tumours result from SB insertional mutagenesis of cancer genes, thus facilitating the identification of genes and pathways that induce disease. SB transposition can easily be controlled to mutagenize any target tissue and can therefore, in principle, be used to induce many of the cancers affecting humans, including those for which little is known about the aetiology. The uses of SB are also not restricted to the mouse and could potentially be used for forward genetic screens in any higher eukaryote in which transgenesis is possible.


Impacts of Maize Domestication and Breeding on Rhizosphere Microbial Community Recruitment from a Nutrient Depleted Agricultural Soil.
Maize domestication and breeding have resulted in drastic and well documented changes in aboveground traits, but belowground effects on root system functioning and rhizosphere microbial communities remain poorly understood, despite their critical importance for nutrient and water acquisition. We investigated the rhizosphere microbial community composition and structure of ten Zea mays accessions along an evolutionary transect (two teosinte, three inbred maize lines, and five modern maize hybrids) grown in nutrient depleted soil from a low input agricultural system. Microbial community analysis revealed significant differences in community composition between soil compartments (proximal vs. distal rhizosphere) and between plant genetic groups (teosinte, inbred, and modern hybrid). Only a small portion of the microbial community was differentially selected across plant genetic groups: 3.7% of prokaryotic community members and 4.9% of fungal community members were significantly associated with a specific plant genetic group. Indicator species analysis showed the greatest differentiation between modern hybrids and the other two plant genetic groups. Co-occurrence network analysis revealed that microbial co-occurrence patterns of the inbred maize lines' rhizosphere were significantly more similar to those of the teosintes than to the modern hybrids. Our results suggest that advances in hybrid development significantly impacted rhizosphere microbial communities and network assembly.


Dissipative assemblies that inhibit their deactivation.
Dissipative self-assembly is a process in which energy-consuming chemical reaction networks drive the assembly of molecules. Prominent examples from biology include the GTP-fueled microtubule and ATP-driven actin assembly. Pattern formation and oscillatory behavior are some of the unique properties of the emerging assemblies. While artificial counterparts exist, researchers have not observed such complex responses. One reason for the missing complexity is the lack of feedback mechanisms of the assemblies on their chemical reaction network. In this work, we describe the dissipative self-assembly of colloids that protect the hydrolysis of their building blocks. The mechanism of inhibition is generalized and explored for other building blocks. We show that we can tune the level of inhibition by the assemblies. Finally, we show that the robustness of the assemblies towards starvation is affected by the degree of inhibition.


A Novel Performance Evaluation Methodology for Single-Target Trackers.
This paper addresses the problem of single-target tracker performance evaluation. We consider the performance measures, the dataset and the evaluation system to be the most important components of tracker evaluation and propose requirements for each of them. The requirements are the basis of a new evaluation methodology that aims at a simple and easily interpretable tracker comparison. The ranking-based methodology addresses tracker equivalence in terms of statistical significance and practical differences. A fully-annotated dataset with per-frame annotations with several visual attributes is introduced. The diversity of its visual properties is maximized in a novel way by clustering a large number of videos according to their visual attributes. This makes it the most sophistically constructed and annotated dataset to date. A multi-platform evaluation system allowing easy integration of third-party trackers is presented as well. The proposed evaluation methodology was tested on the VOT2014 challenge on the new dataset and 38 trackers, making it the largest benchmark to date. Most of the tested trackers are indeed state-of-the-art since they outperform the standard baselines, resulting in a highly-challenging benchmark. An exhaustive analysis of the dataset from the perspective of tracking difficulty is carried out. To facilitate tracker comparison a new performance visualization technique is proposed.


Cellular mechanisms underlying the pharmacological induction of phosphenes.
Visual sensations evoked by stimuli other than luminance changes are called phosphenes. Phosphenes may be an early symptom in a variety of diseases of the retina or of the visual pathways, but healthy individuals may perceive them as well. Phosphene-like phenomena are perhaps the most common side effect reported in clinical pharmacology. Ivabradine, a novel anti-anginal drug that reduces heart-rate by inhibiting the hyperpolarization activated current expressed in cardiac sinoatrial node cells (I(f)) induces phosphenes in some patients. One hypothesis is that ivabradine interacts with the visual system by inhibiting hyperpolarization-activated current in retinal cells (Ih). An Ih current with properties similar to cardiac I(f) has been reported in retinal neurones. Under normal circumstances most of the random fluctuations generated within the retinal circuits do not reach the level of conscious perception because they are filtered out. Presumably, filtering occurs mostly within the retina and one serious candidate for this action is the ability of Ih to act as a negative-feedback mechanism. Ih activation in the membrane of visual cells causes dampening of responses to slow noisy inputs thus tuning the visual system to perceptually more relevant signals of higher frequency. Ih inhibition, by altering at the retinal synapses the filtering of signals generated by thermal breakdown of rhodopsin or other fluctuations, is expected to increase the probability of phosphene occurrence. It is the purpose of the present paper to outline and discuss the features of the visual system and the pharmacological conditions relevant to phosphene perception.


A Reevaluation of the Host Range and Geographical Distribution of Claviceps Species in the United States.
A listing of host and state reports and distribution maps for 11 taxa of Claviceps occurring in the United States, including C. africana, C. cinerea, C. grohii, C. nigricans, C. paspali, C. pusilla, C. purpurea var. purpurea and var. spartinae, C. tripsaci, C. yanagawensis, and C. zizaniae, was prepared based on literature citations and examination of specimens from herbaria. The occurrence of C. ranunculoides is questioned based on examination of conidia and sclerotia from archived specimens. Collections of C. purpurea var. purpurea from grasses in the Pani-coideae were referred to other Claviceps spp. based on occurrence of macroconidia and micro-conidia. C. purpurea var. purpurea was found on 165 grass species within the continental United States and Alaska. The size of conidia of C. purpurea var. purpurea was found to be relatively stable across host and geographical regions. However, conidia of C. purpurea var. purpurea from hosts in the Aveneae and Meliceae (generally associated with wet habitats) were more variable in size and generally larger than those from other tribes in the Pooideae. Claviceps spp. in the continental United States occurred in diverse habitats, including temperate grasslands of the middle to northern latitudes (C. purpurea var. purpurea, C. nigricans) to the middle to southern latitudes (C. pusilla), coastal habitats (C. purpurea var. spartinae, C. ziza-niae), northern wetlands (C. grohii), southern temperate to subtropical grasslands (C. africana, C. paspali, C. tripsaci, C. yanagawensis), and arid southwestern grasslands (C. cinerea).


Application of transfected cell lines in studies of functional receptor subtype selectivity of muscarinic agonists.
Chinese hamster ovary cell lines which stably express individual subtypes of muscarinic acetylcholine receptors (m1-m5) were used to assess the potential selectivity of known muscarinic agonists in effecting coupling of different receptor subtypes to signal transduction mechanisms. Phosphoinositide hydrolysis was measured in m1-, m3- and m5-Chinese hamster ovary cells, whereas inhibition of forskolin-mediated cyclic AMP formation was measured upon the activation of m2 and m4 muscarinic receptors. The two muscarinic agonists pilocarpine and McN-A-343 were notably subtype selective on a functional basis. Pilocarpine was more efficacious in stimulating Phosphoinositide hydrolysis linked to m1 as compared to either m3 or m5 muscarinic receptors. On the other hand, McN-A-343 produced marked inhibition of cyclic AMP formation in m4-Chinese hamster ovary cells but only a small response at m2 receptors. The subtype selectivity of pilocarpine and McN-A-343 in these cases was not due to differences in the level of expression of muscarinic receptors in the various cell lines. In contrast, equalizing receptor number in pairs of cell lines masked apparent selectivities in other cases. Our data highlight the functional discrimination of pilocarpine and McN-A-343 among muscarinic receptor subtypes and emphasize the importance of using cell lines which express an equal number of receptors in the process of searching for subtype selective agonists.


Redefining neuromarketing as an integrated science of influence.
Multiple transformative forces target marketing, many of which derive from new technologies that allow us to sample thinking in real time (i.e., brain imaging), or to look at large aggregations of decisions (i.e., big data). There has been an inclination to refer to the intersection of these technologies with the general topic of marketing as "neuromarketing". There has not been a serious effort to frame neuromarketing, which is the goal of this paper. Neuromarketing can be compared to neuroeconomics, wherein neuroeconomics is generally focused on how individuals make "choices", and represent distributions of choices. Neuromarketing, in contrast, focuses on how a distribution of choices can be shifted or "influenced", which can occur at multiple "scales" of behavior (e.g., individual, group, or market/society). Given influence can affect choice through many cognitive modalities, and not just that of valuation of choice options, a science of influence also implies a need to develop a model of cognitive function integrating attention, memory, and reward/aversion function. The paper concludes with a brief description of three domains of neuromarketing application for studying influence, and their caveats.


Quantitative measurement properties and score interpretation of the Cough Severity Diary in patients with chronic cough.
The Cough Severity Diary (CSD) was developed in accordance with the FDA guidance for patient-reported outcome measures and is focused on capturing the patient's perception of cough in terms of frequency, intensity, and disruption due to their cough. The measure includes a series of seven items asking patients to rate the frequency (three items), intensity (two items), and disruptiveness (two items) of their cough. The instrument was designed to be completed daily before bedtime, has a recall period of 'today,' and responses to items are entered on an 11-point numeric rating scale ranging from 0 to 10 with anchors on each end. The objective of this analysis was to confirm the domain structure of the CSD and assess its reliability, validity, and responsiveness in adult patients with refractory or unexplained chronic cough (RCC/UCC). Criteria for defining meaningful changes in mean weekly CSD total and domain scores in the context of a clinical trial were also developed. Pooled data from a phase II randomized controlled trial of an investigational treatment for RCC/UCC were analyzed. Participants were non-smokers, had RCC/UCC for ⩾1 year, and a baseline cough severity visual analogue scale (VAS) ⩾40 mm. CSD scores (baseline, week 4), were analyzed; the Leicester Cough Questionnaire (LCQ), cough severity VAS, Patient Global Impression of Change (PGIC), and objective cough frequency counts were used for validation. CSD domain structure (Total, Frequency, Intensity, Disruption) was assessed for scoring. A total of 253 participants were included (mean age 60.2; 76% female). Global fit of the three-factor CSD was acceptable. For the CSD total score, internal consistency (α = 0.89) and test-retest reliability (intraclass correlation coefficient = 0.68) were high. CSD total scores were correlated with the LCQ total (r = -0.62) and cough severity VAS (r = 0.84). Participants with a PGIC score of 1 or 2 (most improved groups) had the greatest mean score improvement on the CSD Total (Day 0 to Day 28), supporting responsiveness (similar findings for subscales). A change threshold of ⩾1.3-point reduction on the total and subscale scores is appropriate to define clinically meaningful improvement. The CSD is a reliable, valid, and responsive measure of cough symptom severity in patients with refractory or unexplained chronic cough and fit-for-purpose for assessing changes in cough severity in clinical trials. The reviews of this paper are available via the supplemental material section.


Sex chromosome trisomies are not associated with atypical lateralization for language.
To test the hypothesis that sex chromosome trisomies (SCTs) are associated with reduced left lateralization for language. Using a cross-sectional design, language laterality was measured during an animation description task using functional transcranial Doppler ultrasonography. Data were available for 75 children with an SCT (47,XXX females [n=26], 47,XXY males [n=25], 47,XYY males [n=24]; mean age 11y 4mo [SD 3y 10mo]) and 132 comparison children with typical karyotypes (69 males, 63 females; mean age 9y 1mo [SD 1y 7mo]). Lateralization for language did not differ between the SCT and comparison groups, either in mean laterality index or relative frequency of each laterality category. There were no differences when splitting the group with an SCT by trisomy. Handedness showed no group effects. Our data provide no evidence for disrupted lateralization for language in SCTs. The brain basis of the cognitive phenotype in SCTs is unlikely to be a failure of the left hemisphere to specialize for language, as previously suggested. Children with a sex chromosome trisomy (SCT) have typically lateralized language. This disproves theories linking language problems to hemispheric specialization in SCTs.


The cost and cost-effectiveness of nursing services in health care.
This article examines the literature on cost-effectiveness in nursing, and considers the relationship between this literature and decision-making in health care systems. Researchers have attempted to examine costs and benefits of nurse staffing and nursing interventions for decades. There are strong literatures for some topics, such as advanced practice nursing, clinical practices, occupational health nursing, and workplace training. However, there are gaps in the literature on the cost-effectiveness of nurse staffing patterns, the use of agency personnel, and changes in organizational structure. A review of 6 major health care management textbooks finds few references to cost-effectiveness analysis, suggesting that health care leaders have little education regarding how to conduct or evaluate economic studies. The agenda for nursing research on cost-effectiveness is daunting. Research must be based on large, representative samples; provide clear, compelling results; discuss the importance of both costs and benefits in decision-making; and be published in highly-visible journals.


ATP-consuming and ATP-generating enzymes secreted by pancreas.
Pancreatic acini release ATP in response to various stimuli, including cholecystokinin octapeptide (CCK-8), as we show in the present study. There were indications that pancreatic juice also contains enzymes that could hydrolyze ATP during its passage through the ductal system. The aim of this study was to determine which ATP-degrading and possibly ATP-generating enzymes were present in pancreatic secretion. For this purpose, pancreatic juice was collected from anesthetized rats stimulated with infusion of CCK-8. Purine-converting activities in juice samples were assayed by TLC using either [gamma-(32)P]ATP or (14)C/(3)H-labeled and unlabeled nucleotides as appropriate substrates. Data show that the juice contains the enzyme ecto-nucleoside triphosphate diphosphohydrolase that can hydrolyze both [(14)C]ATP and [(3)H]ADP about equally well, i.e. CD39. Reverse-phase high-performance liquid chromatography analysis additionally shows that this enzyme has broad substrate specificity toward other nucleotides, UTP, UDP, ITP, and IDP. In addition, secretion contains ecto-5'-nucleotidase, CD73, further converting [(3)H]AMP to adenosine. Along with highly active hydrolytic enzymes, there were also ATP-generating enzymes in pancreatic juice, adenylate kinase, and NDP kinase, capable of sequentially phosphorylating AMP via ADP to ATP. Activities of nonspecific phosphatases, nucleotide pyrophosphatase/phosphodiesterases, and adenosine deaminase were negligible. Taken together, CCK-8 stimulation of pancreas causes release of both ATP-consuming and ATP-generating enzymes into pancreatic juice. This newly discovered richness of secreted enzymes underscores the importance of purine signaling between acini and pancreatic ducts lumen and implies regulation of the purine-converting enzymes release.


Reversible carbon monoxide binding and inhibition at the active site of the Fe-only hydrogenase.
Carbon monoxide binding and inhibition have been investigated by electron paramagnetic resonance (EPR) spectroscopy in solution and in crystals of structurally described states of the Fe-only hydrogenase (CpI) from Clostridium pasteurianum. Simulation of the EPR spectrum of the as-isolated state indicates that the main component of the EPR spectrum consists of the oxidized state of the "H cluster" and components due to reduced accessory FeS clusters. Addition of carbon monoxide to CpI in the presence of dithionite results in the inhibition of hydrogen evolution activity, and a characteristic axial EPR signal [g(eff(1)), g(eff(2)), and g(eff(3)) = 2.0725, 2.0061, and 2.0061, respectively] was observed. Hydrogen evolution activity was restored by successive sparging with hydrogen and argon and resulted in samples that exhibited the native oxidized EPR signature that could be converted to the reduced form upon addition of sodium dithionite and hydrogen. To examine the relationship between the spectroscopically defined states of CpI and those observed structurally by X-ray crystallography, we have examined the CpI crystals using EPR spectroscopy. EPR spectra of the crystals in the CO-bound state exhibit the previously described axial signal associated with CO binding. The results indicate that the addition of carbon monoxide to CpI results in a single reversible carbon monoxide-bound species characterized by loss of enzyme activity and the distinctive axial EPR signal.


Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor.
The hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Thirteen different heterozygous germline mutations were identified in patients with HDR. These consisted of three nonsense mutations, six frameshifting deletions, two frameshifting insertions, one missense (Leu348Arg) mutation and one acceptor splice site mutation. The splice site mutation was demonstrated to cause a pre-mRNA processing abnormality leading to the use of an alternative acceptor site 8 bp downstream of the normal site, resulting in a frameshift and prematurely terminated protein. Electrophoretic mobility shift assays (EMSAs) revealed three classes of GATA3 mutations: those that lead to a loss of DNA binding which represent over 90% of all mutations, and involved a loss of the carboxy-terminal zinc finger; those that resulted in a reduced DNA-binding affinity; and those (e.g. Leu348Arg) that did not alter DNA binding or the affinity but likely altered the conformational change that occurs during binding in the DNA major groove as predicted by a three-dimensional modeling. These results elucidate further the molecular mechanisms underlying the altered functions of mutants of this zinc finger transcription factor and their role in causing this developmental anomaly. No mutations were identified in patients with isolated hypoparathyroidism, thereby indicating that GATA3 abnormalities are more likely to result in two or more of the phenotypic features of the HDR syndrome and not in one, such as isolated hypoparathyroidism.


Indirect laryngoscopic approach for injection of botulinum toxin in spasmodic dysphonia.
Spasmodic dysphonia is a focal dystonia that causes a loss of the fine control of intrinsic laryngeal muscles and produces a strained staccato voice. Temporary relief from symptoms has been reported in patients treated with botulinum toxin percutaneously injected into the thyroarytenoid muscle. A newly developed method of treatment differs from reported methods by increasing the accuracy of botulinum toxin placement, reducing soft tissue trauma, and applying basic scientific information about the functional histology of intrinsic laryngeal musculature. Sixteen patients with primarily adductor spasmodic dysphonia were treated. Initial assessment included laryngeal examination by indirect laryngoscopy, videoendoscopy, and stroboscopy, neurology examination (including laryngeal EMG), and vocal function studies with acoustic analysis and aerodynamic studies. A device originally designed for collagen injection allowed the precise microdelivery of toxin to the thyroarytenoid muscle. Indirect laryngoscopy was used to direct the needle, in an attempt to cover a broad area of motor end plates. The minimally effective dose was titrated for each patient, to avoid paralysis and preserve laryngeal function. All patients showed improved voices after treatment. There were no major complications. The basic technique can be performed in the otolaryngologist's office and does not require electromyography equipment or expertise.


Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R).
IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R). More than nine heterozygous mutations, including one compound heterozygous mutation, of the IGF1R gene have been reported in patients with varying degrees of intrauterine and postnatal growth retardation. The objective of the study was the analysis of the IGF1R gene in a short-statured patient. The male patient, with a height of -5.91 sd score (aged 20.3 yr), had consistently elevated circulating serum concentrations of IGF-I. A diagnosis of antibody-negative insulin-requiring diabetes was made at age 14 yr. His deceased sister was also severely short statured (-3.75 sd score). The patient and his sister carried novel, compound heterozygous IGF1R missense mutations, E121K (exon 2) and E234K (exon 3), inherited from the mother and father, respectively. In vitro reconstitution studies demonstrated that neither the E121K nor E234K mutation affected IGF1R prepeptide expression, but levels of the proteolytically cleaved α- and β-subunit were consistently low. As a consequence, each IGF1R variant exhibited significantly reduced IGF-I-induced signal transduction. Correlating to these studies, expression of functional IGF1R and the IGF-I-induced activation of the IGF1R pathway were markedly reduced in the primary dermal fibroblasts established from the patient. Only the second compound heterozygous IGF1R mutations to be identified, the p.E121K/E234K variant is the cause of intrauterine growth retardation and the most severe postnatal growth failure described to date in a patient with IGF1R defects. Whether the mutant IGF1R also contributes to the diabetic phenotype, however, remains to be determined.


Expression profiling of 21 biomolecules in locally advanced nasopharyngeal carcinomas of Caucasian patients.
Since scarce data exist on the pathogenesis of nasopharyngeal carcinoma in Caucasian patients, we attempted to elucidate the responsible molecular pathways in this patient population. Formalin-fixed paraffin-embedded tumor tissue samples from 107 patients, diagnosed with locally-advanced nasopharyngeal carcinoma and treated with chemotherapy or chemo-radiotherapy, were analyzed by immunohistochemistry for the expression of the following proteins: E-cadherin, P-cadherin, Fascin-1, Cyclin D1, COX-2, EGFR, VEGF-A, VEGF-C, VEGFR-2, VEGFR-3, ERCC1, p53, p63, Ki67, MAPT, phospho-p44/42MAPK, PTEN, phospho-AKT, phospho-mTOR, and phospho-GSK-3β. EBER status was assessed by in situ hybridization. The majority of the cases were included in tissue microarray. All stains were performed and assessed centrally by two pathologists. The median follow-up time was 76.8 (42.3 - 99.2) months. Biomolecules expressed in >90% of cases were: p53, COX-2, P-cadherin, EBER, phospho-GSK-3β, and Fascin-1. WHO II+III tumors were more frequently EBER & PTEN positive and VEGF-A negative. Advanced age was significantly associated with positive phospho-GSK-3β and ERCC1 expression; male gender with positive phospho-AKT and phospho-p44/42MAPK; and worse performance status (1 or 2) with negative Ki67, ERCC1, PTEN, and phospho-mTOR expression. Earlier disease stage was closely associated with p63, MAPT, PTEN, and Cyclin D1 positivity. Univariate Cox regression analysis highlighted Cyclin D1 as a negative prognostic factor for disease-free survival (p=0.034) and EBER as a positive one for overall survival (p=0.048). In multivariate analysis, advanced age and stage, poor performance status, and positive ERCC1 emerged as predictors of worse disease-free and overall survival, as opposed to positive phospho-mTOR. Clustering analysis defined two protein-expression groups being predictive of better overall survival (p=0.043). Our study is the first to examine the activation and interaction of established biomolecules and signaling pathways in Caucasian NPC patients in an effort to reveal new therapeutic targets.


Evidence for strong, widespread chlorine radical chemistry associated with pollution outflow from continental Asia.
The chlorine radical is a potent atmospheric oxidant, capable of perturbing tropospheric oxidative cycles normally controlled by the hydroxyl radical. Significantly faster reaction rates allow chlorine radicals to expedite oxidation of hydrocarbons, including methane, and in polluted environments, to enhance ozone production. Here we present evidence, from the CARIBIC airborne dataset, for extensive chlorine radical chemistry associated with Asian pollution outflow, from airborne observations made over the Malaysian Peninsula in winter. This region is known for persistent convection that regularly delivers surface air to higher altitudes and serves as a major transport pathway into the stratosphere. Oxidant ratios inferred from hydrocarbon relationships show that chlorine radicals were regionally more important than hydroxyl radicals for alkane oxidation and were also important for methane and alkene oxidation (>10%). Our observations reveal pollution-related chlorine chemistry that is both widespread and recurrent, and has implications for tropospheric oxidizing capacity, stratospheric composition and ozone chemistry.


Sequence-specific pausing during in vitro DNA replication on double-stranded DNA templates.
Sequence-specific pausing occurs during DNA synthesis catalyzed by the bacteriophage T4 DNA polymerase holoenzyme in the presence of the T4 helix destabilizing protein (gene 32 protein). Two of the six strongest pause sites on a double-stranded bacteriophage fd DNA template are in regions where hairpin helices are predicted to form when the DNA is single stranded. However, the other pause sites are in regions that are not obviously involved in secondary structure. The positions of the DNA chain ends produced at one pause site of each type were determined to within +/- 2 nucleotides. At this resolution, a clustering of sites is observed, suggesting that the polymerase holoenzyme may become destabilized when moving along selected regions of the DNA and then pause at one or more of several closely spaced positions. The addition of the T4 gene 41 protein (a DNA helicase that forms part of the T4 primosome) to the above replication system greatly increases the rate of fork movement and eliminates detectable pausing. In contrast, the addition of the T4 dda protein (a second DNA helicase that increases the rate of fork movement to a similar extent) has no affect on replication fork pausing. This difference could either be due to specific protein-protein interactions formed between the polymerase holoenzyme and the 41 protein or to the highly processive movement of the 41 protein along the displaced DNA strand.


Circulating histones are mediators of trauma-associated lung injury.
Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology. To investigate the pathological roles of circulating histones in trauma-induced lung injury. Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause-effect relationship was studied using cells and mouse models. In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality. This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival outcomes in patients.


Candida albicans Ume6, a filament-specific transcriptional regulator, directs hyphal growth via a pathway involving Hgc1 cyclin-related protein.
The ability of Candida albicans, the most common human fungal pathogen, to transition from yeast to hyphae is essential for pathogenicity. While a variety of transcription factors important for filamentation have been identified and characterized, links between transcriptional regulators of C. albicans morphogenesis and molecular mechanisms that drive hyphal growth are not well defined. We have previously observed that constitutive expression of UME6, which encodes a filament-specific transcriptional regulator, is sufficient to direct hyphal growth in the absence of filament-inducing conditions. Here we show that HGC1, encoding a cyclin-related protein necessary for hyphal growth under filament-inducing conditions, is specifically important for agar invasion, hyphal extension, and formation of true septa in response to constitutive UME6 expression under non-filament-inducing conditions. HGC1-dependent inactivation of Rga2, a Cdc42 GTPase activating protein (GAP), also appears to be important for these processes. In response to filament-inducing conditions, HGC1 is induced prior to UME6 although UME6 controls the level and duration of HGC1 expression, which are likely to be important for hyphal extension. Interestingly, an epistasis analysis suggests that UME6 and HGC1 play distinct roles during early filament formation. These findings establish a link between a key regulator of filamentation and a downstream mechanism important for hyphal formation. In addition, this study demonstrates that a strain expressing constitutive high levels of UME6 provides a powerful strategy to specifically dissect downstream mechanisms important for hyphal development in the absence of complex filament-inducing conditions.


Modulating the properties of multi-functional molecular devices consisting of zigzag gallium nitride nanoribbons by different magnetic orderings: a first-principles study.
Using the non-equilibrium Green's function formalism in combination with density functional theory, we calculated the spin-dependent electronic properties of molecular devices consisting of pristine and hydrogen-terminated zigzag gallium nitride nanoribbons (ZGaNNRs). Computational results show that the proposed ZGaNNR models display multiple functions with perfect spin filtering, rectification, and a spin negative differential resistance (sNDR) effect. Spin-dependent transport properties, spin density and transmission pathways with applied bias values were calculated to understand the spin filter and the sNDR effect. The spin filtering efficiency can be up to -100% or 100% within a large range of biases, and a dual spin filtering effect can also be found in these model devices. The highest rectification ratio reaches 4.9 × 109 in spin-down current of ZGaNNRs with only the passivated nitrogen edge, and only ZGaNNRs with the passivated gallium edge exhibit an obvious sNDR behavior with the largest peak to valley current ratio of 1.25 × 107. The proposed hydrogenated ZGaNNRs can be preferred materials for realizing oscillators, memory circuits and fast switching applications.


Multisensory integration is independent of perceived simultaneity.
The importance of multisensory integration for perception and action has long been recognised. Integrating information from individual senses increases the chance of survival by reducing the variability in the incoming signals, thus allowing us to respond more rapidly. Reaction times (RTs) are fastest when the components of the multisensory signals are simultaneous. This response facilitation is traditionally attributed to multisensory integration. However, it is unclear if facilitation of RTs occurs when stimuli are perceived as synchronous or are actually physically synchronous. Repeated exposure to audiovisual asynchrony can change the delay at which multisensory stimuli are perceived as simultaneous, thus changing the delay at which the stimuli are integrated-perceptually. Here we set out to determine how such changes in multisensory integration for perception affect our ability to respond to multisensory events. If stimuli perceived as simultaneous were reacted to most rapidly, it would suggest a common system for multisensory integration for perception and action. If not, it would suggest separate systems. We measured RTs to auditory, visual, and audiovisual stimuli following exposure to audiovisual asynchrony. Exposure affected the variability of the unisensory RT distributions; in particular, the slowest RTs were either speed up or slowed down (in the direction predicted from shifts in perceived simultaneity). Additionally, the multisensory facilitation of RTs (beyond statistical summation) only occurred when audiovisual onsets were physically synchronous, rather than when they appeared simultaneous. We conclude that the perception of synchrony is therefore independent of multisensory integration and suggest a division between multisensory processes that are fast (automatic and unaffected by temporal adaptation) and those that are slow (perceptually driven and adaptable).


Intracellular signaling pathways required for rat vascular smooth muscle cell migration. Interactions between basic fibroblast growth factor and platelet-derived growth factor.
Intracellular signaling pathways activated by both PDGF and basic fibroblast growth factor (bFGF) have been implicated in the migration of vascular smooth muscle cells (VSMC), a key step in the pathogenesis of many vascular diseases. We demonstrate here that, while bFGF is a weak chemoattractant for VSMCs, it is required for the PDGF-directed migration of VSMCs and the activation of calcium/calmodulin-dependent protein kinase II (CamKinase II), an intracellular event that we have previously shown to be important in the regulation of VSMC migration. Neutralizing antibodies to bFGF caused a dramatic reduction in the size of the intracellular calcium transient normally seen after PDGF stimulation and inhibited both PDGF-directed VSMC migration and CamKinase II activation. Partially restoring the calcium transient with ionomycin restored migration and CamKinase II activation as did the forced expression of a mutant CamKinase II that had been "locked" in the active state by site-directed mutagenesis. These results suggest that bFGF links PDGF receptor stimulation to changes in intracellular calcium and CamKinase II activation, reinforcing the central role played by CamKinase II in regulating VSMC migration.


Antisense oligonucleotides as a potential treatment for brain deficits observed in myotonic dystrophy type 1.
Myotonic dystrophy, or dystrophia myotonica type 1 (DM1), is a multi-systemic disorder and is the most common adult form of muscular dystrophy. It affects not only muscles but also many organs, including the brain. Cerebral impairments include cognitive deficits, daytime sleepiness, and loss of visuospatial and memory functions. The expression of mutated transcripts with CUG repeats results in a gain of toxic mRNA function. The antisense oligonucleotide (ASO) strategy to treat DM1 brain deficits is limited by the fact that ASOs do not cross the blood-brain barrier after systemic administration, indicating that other methods of delivery should be considered. ASO technology has emerged as a powerful tool for developing potential new therapies for a wide variety of human diseases, and its potential has been proven in a recent clinical trial. Targeting DMPK mRNA in neural cells derived from human induced pluripotent stem cells obtained from a DM1 patient with the IONIS 486178 ASO abolished CUG-expanded foci, enabled nuclear redistribution of MBNL1/2, and corrected aberrant splicing. Intracerebroventricular injection of the IONIS 486178 ASO in DMSXL mice decreased the levels of mutant DMPK mRNAs by up to 70% throughout different brain regions. It also reversed behavioral abnormalities following neonatal administration. The present study indicated that the IONIS 486178 ASO targets mutant DMPK mRNAs in the brain and strongly supports the feasibility of a therapy for DM1 patients based on the intrathecal injection of an ASO.


Similarity in joint function limitation in Type 3 von Willebrand's disease and moderate haemophilia A.
Type 3 von Willebrand's disease (VWD) is a rare bleeding diathesis with complete or near complete deficiency of von Willebrand factor (VWF) and low factor VIII (FVIII) levels. In contrast, only FVIII is decreased in haemophilia A (HA). Both disorders are complicated by arthropathy. The purpose of this study was to further clarify the roles of FVIII and VWF: Antigen (VWF:Ag) in joint range of motion (ROM) loss over time. We compared joint ROM loss and other bleeding manifestations in 100 Type 3 VWD subjects (FVIII<5%) and 1814 moderate HA subjects (FVIII 1-5%) within the U.S. Universal Data Collection (UDC) database. High rates of bleeding were reported at baseline. During follow-up, moderate HA patients reported a joint (46% vs. 34%, P < 0.0001) or muscle bleed (27% vs. 16%, P < 0.0001) in a higher proportion of visits than VWD patients. Other bleeds, including mucosal, were reported in a greater proportion of visits among patients with Type 3 VWD than among those with HA (49% vs. 32%, P < 0.0001). Multivariate analysis revealed no difference in joint ROM loss over time in the Type 3 VWD vs. moderate HA populations. A higher FVIII level was protective in both VWD and HA (P < 0.001). Our findings support the hypothesis of primacy of the FVIII level in determining risk of joint haemorrhage, and may help target therapy in Type 3 VWD and moderate HA to prevent joint disability.


Pharmacological evaluation of Dioscorea dumetorum tuber used in traditional antidiabetic therapy.
This study was undertaken to confirm or otherwise disprove the alleged effectiveness of Dioscorea dumetorum tuber in the traditional treatment of clinical diabetes mellitus. Hydroalcoholic extracts of the tuber were fractionated by precipitation or solvent partition and the various extracts or fractions subjected to phytochemical and pharmacological tests. Whereas the alkaloid-containing fraction was hyperglycaemic in fasting normal mice, the whole extract and the fractions containing steroidal derivatives evinced significant hypoglycaemic activities in fasting normal mice or rabbits and in fasting alloxan-diabetic rabbits. The hypoglycaemic action of the glycosidic portion in particular was prompt and potent, in normal as well as in severely alloxan-diabetic rabbits suggesting thereby the possibility of obtaining an agent that could act in conditions of even severe insulin lack.


Beam propagation behavior in a quasi-stadium laser diode.
The beam propagation behavior of a quasi-stadium laser diode is theoretically investigated. The resonator that we analyzed consists of one flat end-mirror, one convex curved end-mirror and two straight side wall mirrors. The cavity dimension is much larger than the oscillation wavelength. We derived one-dimensional Huygen's integral equations for this laser cavity and carried out eigenmode calculations using the Fox and Li mode calculation method taking into account the effect of the side wall reflections and visualized the propagation beams. Unique beam propagation behaviors were obtained. These results well agree with our previous experimental results.


Herpes Simplex Virus Type 1 infection is associated with suicidal behavior and first registered psychiatric diagnosis in a healthy population.
Increasing evidence shows that latent infections and inflammation is associated with cognitive and behavioral changes in humans. This case-control study investigates the association between Herpes Simplex Virus Type 1 (HSV-1) infection and C-reactive Protein (CRP) levels, and psychiatric disorders and suicidal behavior. Public health register data from 81,912 participants in the Danish Blood Donor Study, were reviewed to identify individuals registered with an ICD-10 code of any psychiatric diagnosis, or who had attempted or committed suicide. We found 1,504 psychiatric cases and 353 suicidal cases; for all cases, controls were frequency-matched by age and sex, resulting in 5,336 participants. Plasma samples were analyzed for IgG-class antibodies against HSV-1 and CRP. HSV-1 infection was associated with suicidal behavior (odds-ratio, 1.40; 95% confidence interval [CI] 1.11-1.77). Accounting for temporality, HSV-1 infection was associated with having first psychiatric disorder after the date of blood collection (incidence rate ration, 1.44; 95% CI, 1.05-1.95). No association between CRP and psychiatric disorders or suicidal behavior was found. The finding that HSV-1 was associated with suicidal behavior and first psychiatric disorder indicates that infection may play a role in the etiology and pathogenesis of suicidal behavior and development of psychiatric disorders.


Collecting patient preference information using a Clinical Data Research Network: demonstrating feasibility with idiopathic pulmonary fibrosis.
Purpose: Rare diseases present challenges for accessing patient populations to conduct surveys. Clinical Data Research Networks (CDRNs) offer an opportunity to overcome those challenges by providing infrastructure for accessing patients and sharing data. This study aims to demonstrate the feasibility of collecting patient preference information for a rare disease in a CDRN, using idiopathic pulmonary fibrosis as proof of concept. Patients and methods: Utilizing a cohort of idiopathic pulmonary fibrosis (IPF) patients across a CDRN, a discrete choice experiment was administered via electronic and paper methods to collect patient preference information about benefits and risks of two therapeutic options. Survey data were augmented with data from electronic health records and patient-reported outcome surveys. Results: Thirty-three patients completed the preference experiment. The amount of choice attributable to a benefit of slowing of decline in lung function was 36%. Improving efficacy in terms of lung function was 2.16 times as important as improving efficacy in terms of shortness of breath. In terms of side effects, decreasing risk of gastrointestinal problems was 2.6 times as important as decreasing risk of sun sensitivity and 2.4 times as important as decreasing risk of liver injury. In terms of benefit-risk trade-offs, improving efficacy in terms of lung function was 1.6 times as important as decreasing risk of gastrointestinal problems. Conclusion: This study used IPF as a proof of concept to demonstrate the feasibility of collecting patient preference information in a CDRN. The network was advantageous to the study of patient preferences. Future research should continue to explore pathways for the collection and use of patient preference information across networks. The power of consolidated collection efforts may lead to the ability to use preference data to inform decision-making at the regional, specialty, or individual encounter level.


Yoga in adult cancer: a pilot survey of attitudes and beliefs among oncologists.
Depending on interest, knowledge, and skills, oncologists are adapting clinical behaviour to include integrative approaches, supporting patients to make informed complementary care decisions. The present study sought to improve the knowledge base in three ways: Test the acceptability of a self-reported online survey for oncologists.Provide preliminary data collection concerning knowledge, attitudes, beliefs, and current referral practices among oncologists with respect to yoga in adult cancer.List the perceived benefits of and barriers to yoga intervention from a clinical perspective. A 38-item self-report questionnaire was administered online to medical, radiation, and surgical oncologists in British Columbia. Some of the 29 oncologists who completed the survey (n = 10) reported having recommended yoga to patients to improve physical activity, fatigue, stress, insomnia, and muscle or joint stiffness. Other responding oncologists were hesitant or unlikely to suggest yoga for their patients because they had no knowledge of yoga as a therapy (n = 15) or believed that scientific evidence to support its use is lacking (n = 11). All 29 respondents would recommend that their patients participate in a clinical trial to test the efficacy of yoga. In qualitative findings, oncologists compared yoga with exercise and suggested that it might have similar psychological and physical health benefits that would improve patient capacity to endure treatment. Barriers to and limitations of yoga in adult cancer are also discussed. An online self-report survey is feasible, but has response rate limitations. A small number of oncologists are currently recommending yoga to improve health-related outcomes in adult cancer. Respondents would support clinical yoga interventions to improve the evidence base in cancer patients, including men and women in all tumour groups.


Neuromuscular defects in a Drosophila survival motor neuron gene mutant.
Autosomal recessive spinal muscular atrophy (SMA) is linked to mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated at several levels of mRNA biogenesis and is expressed ubiquitously. Studies in various model organisms have shown that the loss of function of the SMN gene leads to embryonic lethality. The human contains two genes encoding for SMN protein and in patients one of these is disrupted. It is thought the remaining low levels of protein produced by the second SMN gene do not suffice and result in the observed specific loss of lower motor neurons and muscle wasting. The early lethality in the animal mutants has made it difficult to understand why primarily these tissues are affected. We have isolated a Drosophila smn mutant. The fly alleles contain point mutations in smn similar to those found in SMA patients. We find that zygotic smn mutant animals show abnormal motor behavior and that smn gene activity is required in both neurons and muscle to alleviate this phenotype. Physiological experiments on the fly smn mutants show that excitatory post-synaptic currents are reduced while synaptic motor neuron boutons are disorganized, indicating defects at the neuromuscular junction. Clustering of a neurotransmitter receptor subunit in the muscle at the neuromuscular junction is severely reduced. This new Drosophila model for SMA thus proposes a functional role for SMN at the neuromuscular junction in the generation of neuromuscular defects.


A High Omega-3 Fatty Acid Multinutrient Supplement Benefits Cognition and Mobility in Older Women: A Randomized, Double-blind, Placebo-controlled Pilot Study.
Mobility is a key determinant of frailty in older persons, and a variety of dietary factors, such as the omega-3 fatty acid docosahexaenoic acid (DHA), are positively associated with decreased frailty and improved mobility and cognition in older persons. The effects of a multinutrient supplement on mobility and cognition were assessed in postmenopausal women (60-84 years). Participants received either Efalex Active 50+ (1g DHA, 160 mg eicosapentaenoic acid, 240 mg Ginkgo biloba, 60 mg phosphatidylserine, 20mg d-α tocopherol, 1mg folic acid, and 20 µg vitamin B12 per day; N = 15) or placebo (N = 12) for 6 months. Mobility was assessed by VICON 9 motion capture camera system synchronized with Kistler force plates, cognitive performance by computerized cognitive function tests, and blood fatty acid levels by pin-prick analysis. Significant effects of treatment were seen in two of the four cognitive tests, with shorter mean latencies in a motor screening task (p < .05) and more words remembered (p < .03), and one of the three primary mobility measures with improved habitual walking speed (p < .05). Compared with the placebo group, supplementation also resulted in significantly higher blood DHA levels (p < .02). In this pilot study, multinutrient supplementation improved cognition and mobility in able older females at clinically relevant levels, suggesting a potential role in reducing the decline to frailty.


Patients with typical laboratory features of autoimmune hepatitis rarely need a liver biopsy for diagnosis.
The importance of histologic analysis of biopsy samples in the diagnosis and management of patients with autoimmune hepatitis (AIH) is unclear. Patients with AIH were identified from a 10-year database. Individuals with overlap syndromes and decompensated liver disease were excluded. The proportion of patients who fulfilled the new simplified criteria for AIH was calculated. A total of 257 patients (203 female) with a median age of 52 years (interquartile range, 39-63 y) were diagnosed with AIH. Overall, 183 of 257 (71%) were positive for antinuclear antibodies, 116 (45%) had positive smooth muscle antibodies, and 29 of 257 (11%) were seronegative. A total of 250 (97%) patients had increased levels of autoantibodies and/or γ-globulins. In 95% (243 of 257 cases), the histology was compatible with AIH whereas 5% (14 cases) had atypical histology. Overall, 77% had a score of at least 6, indicating probable or definite AIH according to most recent criteria; 22% were diagnosed with AIH with less than 6 points and 1 patient had nonalcoholic steatohepatitis based on biopsy analysis. Immunosuppression occurred in 93% of patients. Patients with atypical versus compatible histology were similar in terms of seronegativity or γ-globulins; 86% (12 of 14) received immunosuppressive therapy despite atypical histology. Most patients with features of AIH, based on laboratory analyses, are likely to have a compatible liver histology. Few patients have atypical histology and these findings have little impact on patient management. These findings indicate biopsy samples might not need to be collected from patients who meet other clinical criteria for AIH.


Daytime sleepiness and other sleep disorders in Parkinson's disease.
PD is associated with a variety of sleep problems. The dopamine agonists (DA) pramipexole and ropinirole were recently implicated in causing "sleep attacks" and motor vehicle accidents. In order to determine the overall rate of subjective sleep problems in PD and to determine if any factors, including specific medications, correlate with sleep pathology, the authors surveyed consecutive patients with PD seen over a 3-month period in a Movement Disorders Clinic. The authors collected demographic and medication data, and the patients completed the Epworth Sleepiness Scale (ESS), questions assessing the presence of restless legs syndrome (RLS), a modified National Sleep Foundation sleep survey, and specific questions regarding falling asleep while driving. A total of 320 patients completed the questionnaire. The authors eliminated 17, six for incomplete data and 11 for having a primary diagnosis other than PD. The mean age of the remaining 303 patients was 67.1 +/- 10.7 years, and the mean duration of PD was 9.1 +/- 5.7 years. The ESS scores averaged 11.1 +/- 5.9, and in 50.2% of patients the score was abnormally high (>10). Stepwise regression analysis found that sleepiness correlated with longer duration of PD (p < 0.001), more advanced PD (p < 0.004), male sex (p < 0.001), and the use of any DA (p < 0.003). The soporific effects of the three most common DA (pramipexole, ropinirole, and pergolide) were similar. Falling asleep while driving was reported by 63/279 (22.6%) of current drivers and correlated with higher ESS scores (p < 0.05). Other sleep disorders, including RLS, were also frequently reported. Daytime sleepiness is common in PD and correlates with more advanced and longer duration of PD, and male sex. The DA were also independently associated with daytime sleepiness, but in this group, no single DA was more culpable than the others.


Stabilization of supramolecular membrane protein-lipid bilayer assemblies through immobilization in a crystalline exoskeleton.
Artificial native-like lipid bilayer systems constructed from phospholipids assembling into unilamellar liposomes allow the reconstitution of detergent-solubilized transmembrane proteins into supramolecular lipid-protein assemblies called proteoliposomes, which mimic cellular membranes. Stabilization of these complexes remains challenging because of their chemical composition, the hydrophobicity and structural instability of membrane proteins, and the lability of interactions between protein, detergent, and lipids within micelles and lipid bilayers. In this work we demonstrate that metastable lipid, protein-detergent, and protein-lipid supramolecular complexes can be successfully generated and immobilized within zeolitic-imidazole framework (ZIF) to enhance their stability against chemical and physical stressors. Upon immobilization in ZIF bio-composites, blank liposomes, and model transmembrane metal transporters in detergent micelles or embedded in proteoliposomes resist elevated temperatures, exposure to chemical denaturants, aging, and mechanical stresses. Extensive morphological and functional characterization of the assemblies upon exfoliation reveal that all these complexes encapsulated within the framework maintain their native morphology, structure, and activity, which is otherwise lost rapidly without immobilization.


A possible primordial peptide cycle.
alpha-Amino acids can undergo peptide formation by activation with carbon monoxide (CO) under hot aqueous conditions in the presence of freshly coprecipitated colloidal (Fe,Ni)S. We now show that CO-driven peptide formation proceeds concomitantly with CO-driven, N-terminal peptide degradation by racemizing N-terminal hydantoin and urea derivatives to alpha-amino acids. This establishes a peptide cycle with closely related anabolic and catabolic segments. The hydantoin derivative is a purin-related heterocycle. The (Fe,Ni)S-dependent urea hydrolysis could have been the evolutionary precursor of the nickelenzyme urease. The results support the theory of a chemoautotrophic origin of life with a CO-driven, (Fe,Ni)S-dependent primordial metabolism.


A high-level expression of CYP2A in the lung of the suncus (Suncus murinus) and its role in the activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
Northern blot analysis of mRNA prepared from the lung of Suncus murinus (suncus), which was classified as an ancestor of primates, revealed that the expression level of cytochrome P450 2A (CYP2A) mRNA was about 100-fold higher than in the lung from rats and mice. To confirm that the pulmonary CYP2A of the suncus had a catalytic activity, the metabolism of a specific substrate for CYP2A6, (+)-cis-3,5-dimethyl-2-(3-pyridyl) thiazolidin-4-one hydrochloride (SM-12502), was determined. The intrinsic clearance for SM-12502 S-oxidation by the suncus lung microsomes was calculated to be 99-fold higher than that by rat liver microsomes. The mutagen-producing activity of a 9,000 g supernatant fraction prepared from suncus lung was examined using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as a promutagen. The results showed that the suncus lung possessed 82-fold higher mutagen-producing activity than the rat lung, indicating that NNK was efficiently activated by the CYP2A isoform expressed in the suncus lung and that the suncus was a sensitive animal species to the genotoxicity of NNK contained in tobacco smoke.


Determinants of variations in initial treatment strategies for stable ischemic heart disease.
The ratio of revascularization to medical therapy (referred to herein as the revascularization ratio) for the initial treatment of stable ischemic heart disease varies considerably across hospitals. We conducted a comprehensive study to identify patient, physician and hospital factors associated with variations in the revascularization ratio across 18 cardiac centres in the province of Ontario. We also explored whether clinical outcomes differed between hospitals with high, medium and low ratios. We identified all patients in Ontario who had stable ischemic heart disease documented by index angiography performed between Oct. 1, 2008, and Sept. 30, 2011, at any of the 18 cardiac centres in the province. We classified patients by initial treatment strategy (medical therapy or revascularization). Hospitals were classified into equal tertiles based on their revascularization ratio. The primary outcome was all-cause mortality. Patient follow-up was until Dec. 31, 2012. Hierarchical logistic regression models identified predictors of revascularization. Multivariable Cox proportional hazards models, with a time-varying covariate for actual treatment received, were used to evaluate the impact of the revascularization ratio on clinical outcomes. Variation in revascularization ratios was twofold across the hospitals. Patient factors accounted for 67.4% of the variation in revascularization ratios. Physician and hospital factors were not significantly associated with the variation. Significant patient-level predictors of revascularization were history of smoking, multivessel disease, high-risk findings on noninvasive stress testing and more severe symptoms of angina (v. no symptoms). Treatment at hospitals with a high revascularization ratio was associated with increased mortality compared with treatment at hospitals with a low ratio (hazard ratio 1.12, 95% confidence interval 1.03-1.21). Most of the variation in revascularization ratios across hospitals was warranted, in that it was driven by patient factors. Nonetheless, the variation was associated with potentially important differences in mortality.


A Universal Isotherm Model to Capture Adsorption Uptake and Energy Distribution of Porous Heterogeneous Surface.
The adsorbate-adsorbent thermodynamics are complex as it is influenced by the pore size distributions, surface heterogeneity and site energy distribution, as well as the adsorbate properties. Together, these parameters defined the adsorbate uptake forming the state diagrams, known as the adsorption isotherms, when the sorption site energy on the pore surfaces are favorable. The available adsorption models for describing the vapor uptake or isotherms, hitherto, are individually defined to correlate to a certain type of isotherm patterns. There is yet a universal approach in developing these isotherm models. In this paper, we demonstrate that the characteristics of all sorption isotherm types can be succinctly unified by a revised Langmuir model when merged with the concepts of Homotattic Patch Approximation (HPA) and the availability of multiple sets of site energy accompanied by their respective fractional probability factors. The total uptake (q/q*) at assorted pressure ratios (P/P s ) are inextricably traced to the manner the site energies are spread, either naturally or engineered by scientists, over and across the heterogeneous surfaces. An insight to the porous heterogeneous surface characteristics, in terms of adsorption site availability has been presented, describing the unique behavior of each isotherm type.