2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren's Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts.
To develop and validate an international set of classification criteria for primary Sjögren's syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS. We assigned preliminary importance weights to a consensus list of candidate criteria items, using multi-criteria decision analysis. We tested and adapted the resulting draft criteria using existing cohort data on primary SS cases and non-SS controls, with case/non-case status derived from expert clinical judgment. We then validated the performance of the classification criteria in a separate cohort of patients. The final classification criteria are based on the weighted sum of 5 items: anti-SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm2 , each scoring 3; an abnormal ocular staining score of ≥5 (or van Bijsterveld score of ≥4), a Schirmer's test result of ≤5 mm/5 minutes, and an unstimulated salivary flow rate of ≤0.1 ml/minute, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS. Sensitivity and specificity against clinician-expert-derived case/non-case status in the final validation cohort were high, i.e., 96% (95% confidence interval [95% CI] 92-98%) and 95% (95% CI 92-97%), respectively. Using methodology consistent with other recent ACR/EULAR-approved classification criteria, we developed a single set of data-driven consensus classification criteria for primary SS, which performed well in validation analyses and are well-suited as criteria for enrollment in clinical trials.


Handshake antimicrobial stewardship as a model to recognize and prevent diagnostic errors.
Few studies describe the impact of antimicrobial stewardship programs (ASPs) on recognizing and preventing diagnostic errors. Handshake stewardship (HS-ASP) is a novel ASP model that prospectively reviews hospital-wide antimicrobial usage with recommendations made in person to treatment teams. The purpose of this study was to determine if HS-ASP could identify and intervene on potential diagnostic errors for children hospitalized at a quaternary care children's hospital. Previously self-identified "Great Catch" (GC) interventions by the Children's Hospital Colorado HS-ASP team from 10/2014 through 5/2018 were retrospectively reviewed. Each GC was categorized based on the types of recommendations from HS-ASP, including if any diagnostic recommendations were made to the treatment team. Each GC was independently scored using the "Safer Dx Instrument" to determine presence of diagnostic error based on a previously determined cut-off score of ≤1.50. Interrater reliability for the instrument was measured using a randomized subset of one third of GCs. During the study period, there were 162 GC interventions. Of these, 65 (40%) included diagnostic recommendations by HS-ASP and 19 (12%) had a Safer Dx Score of ≤1.50, (Κ=0.44; moderate agreement). Of those GCs associated with diagnostic errors, the HS-ASP team made a diagnostic recommendation to the primary treatment team 95% of the time. Handshake stewardship has the potential to identify and intervene on diagnostic errors for hospitalized children.


Legalon® SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning.
More than 90% of all fatal mushroom poisonings worldwide are due to amatoxin containing species that grow abundantly in Europe, South Asia, and the Indian subcontinent. Many cases have also been reported in North America. Initial symptoms of abdominal cramps, vomiting, and a severe cholera-like diarrhea generally do not manifest until at least six to eight hours following ingestion and can be followed by renal and hepatic failure. Outcomes range from complete recovery to fulminant organ failure and death which can sometimes be averted by liver transplant. There are no controlled clinical studies available due to ethical reasons, but uncontrolled trials and case reports describe successful treatment with intravenous silibinin (Legalon® SIL). In nearly 1,500 documented cases, the overall mortality in patients treated with Legalon® SIL is less than 10% in comparison to more than 20% when using penicillin or a combination of silibinin and penicillin. Silibinin, a proven antioxidative and anti-inflammatory acting flavonolignan isolated from milk thistle extracts, has been shown to interact with specific hepatic transport proteins blocking cellular amatoxin re-uptake and thus interrupting enterohepatic circulation of the toxin. The addition of intravenous silibinin to aggressive intravenous fluid management serves to arrest and allow reversal of the manifestation of fulminant hepatic failure, even in severely poisoned patients. These findings together with the available clinical experience justify the use of silibinin as Legalon® SIL in Amanita poisoning cases.


The validity of capillary blood sampling in the determination of human growth hormone concentration during exercise in men.
Studies measuring human growth hormone (hGH) in blood during exercise have mainly used venous sampling. The invasive nature of this procedure makes evaluation of hGH impossible in various exercise environments. To determine whether capillary sampling could offer an alternative sampling method. Capillary and venous blood samples were collected for determination of hGH at the end of each exercise stage during an incremental exercise test in 16 male club level competitive cyclists (mean (SD) age 30.8 (8.0) years, body mass 72.2 (7.1) kg, body fat 12.9 (3.5)%, peak oxygen consumption 4.18 (0.46) l x min(-1)). Linear regression, from a plot of venous v capillary blood hGH concentration, showed a correlation coefficient of r = 0.986 (p<0.001). When geometric means and log transformations were used, a coefficient of variation of 14.2% was demonstrated between venous and capillary flow for hGH concentration. The mean ratio limits of agreement were 0.62 (1.72)-that is, 95% of the ratios were contained between 0.36 and 1.07, with a mean of 0.62. Capillary blood sampling is an acceptable alternative to venous sampling for determining hGH concentration during rest and exercise. Sample sites should not be used interchangeably: one site should be chosen and its use standardised.


Living with a stranger's organ--views of the public and transplant recipients.
This comprehensive article is based on three previous studies on people's reactions on receiving transplants of various kinds: a survey of the public, in-depth interviews with informants recruited from this survey and two other surveys, and in-depth interviews with heart and kidney recipients. The ideas and reactions of the public, when confronted with the issue of receiving a transplant in a hypothetic situation, vary from magical thinking to a conception of the body as an object in need of repair. The actual recipients show a similar variation in their reactions as the public. However, there are some differences between the two groups that probably depend on the patient selection for transplantation, reality factors, acclimatization factors, and defense strategies to master anxiety-provoking thoughts about the donor and transplant. The most constructive of the ideas about the donor seems to be identification with positive traits, such as generosity and solidarity.


Early and midterm outcomes of bioresorbable vascular scaffolds for ostial coronary lesions: insights from the GHOST-EU registry.
We aimed to investigate the outcomes of bioresorbable vascular scaffolds (BVS) in coronary ostial lesions. Ostial lesions represent a challenging angiographic subset, with higher event rates compared with non-ostial lesions. BVS might be associated with advantages over the long term, but their safety in this setting remains to be explored. Procedural and 12-month follow-up data from consecutive patients treated with BVS for lesions located at the ostium of the right (RCA), left anterior (LAD) or circumflex (LCX) coronary in 11 European centres were collected. The primary device-oriented endpoint was defined as a combination of cardiovascular death, target vessel myocardial infarction or target lesion revascularisation. The database included a total of 1,549 lesions in 1,304 patients with a mean age of 62±11years. There were 90 ostial lesions (5.8%) in 84 patients (6.4%) located at the ostial RCA (14; 16%), LCX (29; 32%), or LAD (47; 52%). Patients presenting with ostial lesions did not differ from the remaining cohort except for a higher incidence of prior revascularisation. Predilation was performed in 97% of the lesions (vs. 96% in non-ostial, p=0.618), post-dilation in 43% (versus 58% in the non-ostial group, p=0.008). At quantitative coronary angiography, treatment of ostial lesions was associated with higher residual stenosis (30% [23-41] vs. 26% [20-37], p=0.035), but no difference in minimum lumen diameter existed (p=0.447). Follow-up data were available at 385 [362-465] days. The 12-month Kaplan-Meier estimated rates of scaffold thrombosis were 4.9% and 2.0% (ostial and non-ostial lesion groups, respectively, log-rank p=0.005). The device-oriented composite endpoint occurred, respectively, in 12.6% and 4.6% at 12 months (log-rank p=0.001). Treatment of ostial lesions was an independent predictor of this endpoint (p=0.0025, HR 2.65 [1.41-4.97]). In combination with a suboptimal implantation technique, treatment of coronary ostial lesions was an independent predictor of clinical events in a cohort of patients treated with BVS.


Giving care to people with symptoms of AIDS in rural sub-Saharan Africa.
In rural sub-Saharan Africa, most care for patients with AIDS is provided at home by relatives. Caring for those with AIDS is assumed to be a substantial burden, but little is known from the perspectives of those who provide the care. In this paper we use interviews with caregivers, supplemented with survey data from a larger study in rural Malawi, to investigate this issue. We focus on the caregivers' diagnoses of the illness of their patients, the type and duration of the care they provided, the support they received from relatives and other members of the community, and the extent to which caregiving was experienced as an emotional, physical, and financial burden. Although none of the caregivers knew of a formal diagnosis and few explicitly named their relative's disease as AIDS, most appeared to suspect it. They described the illness using the typical symptoms of AIDS as they are locally understood and sometimes related the illness to their patient's sexual history. The care, typically given by close female relatives of the patient, was limited to the care that would be given to anyone who was seriously ill. What was striking, however, was the compassion of the caregivers and the attempts they made to provide the best care possible in their circumstances. For most caregivers, kin and members of the community provided social, moral, and physical support, as well as modest financial assistance. Caregiving was physically and emotionally demanding and confined the caregivers to their home, but most caregivers did not consider caregiving a problem primarily because the patients were close relatives. The financial impact of caregiving was typically modest because the caregivers had very little income and few possessions to sell.


The reaction mechanism for CD38. A single intermediate is responsible for cyclization, hydrolysis, and base-exchange chemistries.
Human recombinant CD38 catalyzes the formation of both cyclic ADP-ribose and ADP-ribose products from NAD+ and hydrolyzes cyclic ADP-ribose to ADP-ribose. The corresponding GDP products are formed from NGD+. The enzyme was characterized by substrate and inhibition kinetics, exchange studies, rapid-quench reactions, and stopped-flow-fluorescence spectroscopy to establish the reaction mechanism and energetics for individual steps. Noncyclizable substrates NMN+ and nicotinamide-7-deaza-hypoxanthine dinucleotide (7-deaza NHD+) were rapidly hydrolyzed by the enzyme. The kcat for NMN+ was 5-fold higher than that of NAD+ and has the greatest reported kcat of any substrate for CD38. 7-deaza-NHD+ was hydrolyzed at approximately one-third the rate of NHD+ but does not form a cyclic product. These results establish that a cyclic intermediate is not required for substrate hydrolysis. The ratio of methanolysis to hydrolysis for cADPR and NAD+ catalyzed by CD38 increases linearly with MeOH concentration. Both reactions produce predominantly the beta-methoxy riboside compound, with a relative nucleophilicity of MeOH to H2O of 11. These results indicate the existence of a stabilized cationic intermediate for all observed chemistries in the active site of CD38. The partitioning of this intermediate between cyclization, hydrolysis, and nicotinamide-exchange unites the mechanisms of CD38 chemistries. Steady-state and pre-steady-state parameters for the partition and exchange mechanisms allowed full characterization of the reaction coordinate. Stopped-flow methods indicate a burst of cGDPR formation followed by the steady-state reaction rate. A lag phase, which was NGD+ concentration dependent, was also observed. The burst size indicates that the dimeric enzyme has a single catalytic site formed by two subunits. Pre-steady-state quench experiments did not detect covalent intermediates. Nicotinamide hydrolysis of NGD+ precedes cyclization and the chemical quench decomposes the enzyme-bound species to a mixture of cyclic and hydrolysis products. The time dependence of this ratio indicated that nicotinamide bond-breakage occurs 4 times faster than the conversion of the intermediate to products. Product release is the overall rate-limiting step for enzyme reaction with NGD+.


A double-blind placebo controlled trial of Efamol Marine on skin and joint symptoms of psoriatic arthritis.
Fish oil may be beneficial in the treatment of psoriasis and in RA. We examined the potential benefit of Efamol Marine, a combination of evening primrose oil and fish oil in the treatment of 38 patients with PsA. Patients with PsA were entered in a double-blind placebo controlled study and received either 12 Efamol Marine capsules or 12 placebo capsules daily for 9 months. All patients received placebo capsules for a further 3 months. At month 3 of the study patients were asked to reduce their intake of NSAIDs and maintain that decrease provided there was no worsening of their joint symptoms. Clinical assessments of skin and joint disease severity and activity were performed at 0, 1, 3, 6, 9 and 12 months. All measures of skin disease activity including severity, percentage body affected and itch were unchanged by Efamol Marine. The NSAID requirement remained the same between both treatment groups. In addition, there was no change demonstrated in the activity of arthritis as measured by duration of morning stiffness. Ritchie articular index, number of active joints, ESR and CRP. However, a rise in serum TXB2 was observed in the active group during the placebo phase; in addition a fall in leukotriene B4 production occurred during the active phase period followed by a marked rise during the placebo phase suggesting some laboratory documented anti-inflammatory effect. In conclusion, this study suggests that Efamol Marine may alter prostaglandin metabolism in patients with PsA, although it did not produce a clinical improvement and did not allow reduction in NSAID requirement. A larger dose of essential fatty acid may be needed to produce a clinical benefit.


CD49b inhibits osteogenic differentiation and plays an important role in osteosarcoma progression.
Osteosarcoma is a cancer whose cell of origin lies in the differentiation pathway between the mesenchymal stem cell (MSC) and the osteoblast (OB). In this study, we sought to determine if surface markers associated with osteoblastic differentiation are involved in osteosarcoma progression. cDNA expression arrays were performed on MSCs and osteoblasts to identify differentially expressed genes. The specificity of candidate genes for osteoblast differentiation was assessed through time course experiments in differentiation media with confirmation utilizing CD49b transfected MSCs. In addition, CD49b was transfected into osteosarcoma cell lines to determine its impact on cell proliferation, motility, and invasion. Finally, the expression of CD49b was assessed in osteosarcoma patient samples and correlated with survival outcomes. cDNA expression arrays identified a list of genes differentially expressed between MSCs and osteoblasts with a subset of those genes encoding cell surface proteins. Three genes were selected for further analysis, based on qPCR validation, but only CD49b was selective for osteoblastic differentiation. Forced expression of CD49b in MSCs led to delayed osteoblastic differentiation. Down-regulation of CD49b expression in osteosarcoma cell lines resulted in inhibition of their migration and invasion capacity. CD49b expression in osteosarcoma patients was associated with presence of metastases and inferior 5 year overall survival (31.4% vs. 57.4%, p=0.03). Surface proteins involved in osteosarcoma cell differentiation, such as CD49b, have the potential to serve as prognostic biomarkers, and may lead to the identification of new therapeutic targets.


A carbonic anhydrase inhibitor induces bicarbonate-reversible suppression of electron transfer in pea photosystem 2 membrane fragments.
The effects of suppression of the carbonic anhydrase (CA) activity by a CA-inhibitor, acetazolamide (AA), on the photosynthetic activities of photosystem II (PS II) particles from higher plants were investigated. AA along with CA-activity inhibits the PS II photosynthetic electron transfer and the AA-induced suppression is totally reversed by the addition of bicarbonate (3-5 mM). Similar effect of recovery in the PS II photosynthetic activity was also revealed upon the addition of known artificial electron donors (potassium ferrocyanide and TMPD). Significance and possible functions of CA for the PS II donor side are discussed.


Comparative analysis of endoscopic third ventriculostomy trajectories in pediatric cases.
Endoscopic third ventriculostomy (ETV) has become a widely used method for CSF diversion when treating obstructive hydrocephalus. There are multiple recommendations on the transcortical ETV entry points, and some are specifically designed to provide a trajectory that avoids displacement to the eloquent periventricular structures. However, the morphology of the ventricular system is highly variable in hydrocephalus, and therefore a single best ETV trajectory may not be applicable to all cases. In the current study, 3 frequently quoted ETV entry points are compared in a cohort of pediatric cases with different degrees of ventriculomegaly. The images of 30 consecutive pediatric patients with varying degrees of ventriculomegaly were reviewed. Three-dimensional models were created using radiological analysis of anatomical detail and preoperative MRI scans in order to simulate 3 frequently quoted ETV trajectories for rigid neuroendoscopes. These trajectories were characterized based on the frequency and depth of tissue displacement to structures such as the fornix, caudate nucleus, genu of the internal capsule, and thalamus. The results are stratified based on ventricle size using the frontal horn ratio (FHR). Eloquent areas were displaced in nearly all analyzed entry points (97%-100%). Stratifying the data based on ventricle size revealed that (1) lateral structures were more likely to be displaced in cases of intermediate ventriculomegaly (FHR < 0.4) using all 3 trajectories, whereas (2) the fornix was less likely to be displaced using more posteriorly placed trajectories for severe ventriculomegaly (FHR > 0.4). Allowing for minimal (2.4 mm) tissue displacement, a more posterior entry point was less traumatic for severe ventriculomegaly. There is no single best ETV trajectory that fully avoids displacement of the eloquent periventricular structures. Larger ventricles require a more posteriorly placed entry point in order to reduce injury to the eloquent structures, and intermediate ventricles would dictate a medial entry point. These results suggest that the optimal entry point should be selected on a case-by-case basis after incorporating ventricle size.


Does pupil constriction under blue and green monochromatic light exposure change with age?
Many nonvisual functions are regulated by light through a photoreceptive system involving melanopsin-expressing retinal ganglion cells that are maximally sensitive to blue light. Several studies have suggested that the ability of light to modulate circadian entrainment and to induce acute effects on melatonin secretion, subjective alertness, and gene expression decreases during aging, particularly for blue light. This could contribute to the documented changes in sleep and circadian regulatory processes with aging. However, age-related modification in the impact of light on steady-state pupil constriction, which regulates the amount of light reaching the retina, is not demonstrated. We measured pupil size in 16 young (22.8±4 years) and 14 older (61±4.4 years) healthy subjects during 45-second exposures to blue (480 nm) and green (550 nm) monochromatic lights at low (7×10(12) photons/cm2/s), medium (3×10(13) photons/cm2/s), and high (10(14) photons/cm2/s) irradiance levels. Results showed that young subjects had consistently larger pupils than older subjects for dark adaptation and during all light exposures. Steady-state pupil constriction was greater under blue than green light exposure in both age groups and increased with increasing irradiance. Surprisingly, when expressed in relation to baseline pupil size, no significant age-related differences were observed in pupil constriction. The observed reduction in pupil size in older individuals, both in darkness and during light exposure, may reduce retinal illumination and consequently affect nonvisual responses to light. The absence of a significant difference between age groups for relative steady-state pupil constriction suggests that other factors such as tonic, sympathetic control of pupil dilation, rather than light sensitivity per se, account for the observed age difference in pupil size regulation. Compared to other nonvisual functions, the light sensitivity of steady-state pupil constriction appears to remain relatively intact and is not profoundly altered by age.


Biomechanical Characteristics between Bionic Shoes and Normal Shoes during the Drop-Landing Phase: A Pilot Study.
With the development of unstable footwear, more research has focused on the advantages of this type of shoe. This type of shoe could improve the muscle function of the lower limb and prevent injury risks in dynamic situations. Therefore, the purpose of this study was to investigate differences in lower-limb kinetics and kinematics based on single-leg landing (SLL) using normal shoes (NS) and bionic shoes (BS). The study used 15 male subject volunteers (age 23.4 ± 1.14 years, height 177.6 ± 4.83cm, body weight (BW) 73.6 ± 7.02 kg). To ensure the subject standardization of the participants, there were several inclusion criteria used for selection. There were two kinds of experimental shoes used in the landing experiment to detect the change of lower limbs when a landing task was performed. Kinetics and kinematic data were collected during an SLL task, and statistical parametric mapping (SPM) analysis was used to evaluate the differences between NS and BS. We found that the flexion and extension angles of the knee (p = 0.004) and hip (p = 0.046, p = 0.018) joints, and the dorsiflexion and plantarflexion of ankle (p = 0.031) moment were significantly different in the sagittal planes. In the frontal plane, the eversion and inversion of the ankle (p = 0.016), and the abduction and adduction of knee (p = 0.017, p = 0.007) angle were found significant differences. In the horizontal plane, the external and internal rotation of hip (p = 0.036) and knee (p < 0.001, p = 0.029) moment were found significant differences, and knee angle (p = 0.043) also. According to our results, we conclude that using BS can cause bigger knee and hip flexion than NS. Also, this finding indicates that BS might be considered to reduce lower-limb injury risk during the SLL phase.


Rat8p/Dbp5p is a shuttling transport factor that interacts with Rat7p/Nup159p and Gle1p and suppresses the mRNA export defect of xpo1-1 cells.
In a screen for temperature-sensitive mutants of Saccharomyces cerevisiae defective for mRNA export, we previously identified the essential DEAD-box protein Dbp5p/Rat8p and the nucleoporin Rat7p/Nup159p. Both are essential for mRNA export. Here we report that Dbp5p and Rat7p interact through their Nterminal domains. Deletion of this portion of Rat7p (Rat7pDeltaN) results in strong defects in mRNA export and eliminates association of Dbp5p with nuclear pores. Overexpression of Dbp5p completely suppressed the growth and mRNA export defects of rat7DeltaN cells and resulted in weaker suppression in cells carrying rat7-1 or the rss1-37 allele of GLE1. Dbp5p interacts with Gle1p independently of the N-terminus of Dbp5p. Dbp5p shuttles between nucleus and cytoplasm in an Xpo1p-dependent manner. It accumulates in nuclei of xpo1-1 cells and in cells with mutations affecting Mex67p (mex67-5), Gsp1p (Ran) or Ran effectors. Overexpression of Dbp5p prevents nuclear accumulation of mRNA in xpo1-1 cells, but does not restore growth, suggesting that the RNA export defect of xpo1-1 cells may be indirect. In a screen for high-copy suppressors of the rat8-2 allele of DBP5, we identified YMR255w, now called GFD1. Gfd1p is not essential, interacts with Gle1p and Rip1p/Nup42p, and is found in the cytoplasm and at the nuclear rim.


Biomarkers Associated With Leishmania infantum Exposure, Infection, and Disease in Dogs.
Canine leishmaniosis (CanL) is a vector-borne disease caused by the protozoan Leishmania (Leishmania) infantum species [syn. L. (L.) infantum chagasi species in the Americas] which is transmitted by the bite of a female phlebotomine sand fly. This parasitosis is endemic and affect millions of dogs in Asia, the Americas and the Mediterranean basin. Domestic dogs are the main hosts and the main reservoir hosts for human zoonotic leishmaniosis. The outcome of infection is a consequence of intricate interactions between the protozoan and the immunological and genetic background of the host. Clinical manifestations can range from subclinical infection to very severe disease. Early detection of infected dogs, their close surveillance and treatment are essential to control the dissemination of the parasite among other dogs, being also a pivotal element for the control of human zoonotic leishmaniosis. Hence, the identification of biomarkers for the confirmation of Leishmania infection, disease and determination of an appropriate treatment would represent an important tool to assist clinicians in diagnosis, monitoring and in giving a realistic prognosis to subclinical infected and sick dogs. Here, we review the recent advances in the identification of Leishmania infantum biomarkers, focusing on those related to parasite exposure, susceptibility to infection and disease development. Markers related to the pathogenesis of the disease and to monitoring the evolution of leishmaniosis and treatment outcome are also summarized. Data emphasizes the complexity of parasite-host interactions and that a single biomarker cannot be used alone for CanL diagnosis or prognosis. Nevertheless, results are encouraging and future research to explore the potential clinical application of biomarkers is warranted.


Role of metal-oxide interface in determining the spin polarization of magnetic tunnel junctions
The role of the metal-oxide interface in determining the spin polarization of electrons tunneling from or into ferromagnetic transition metals in magnetic tunnel junctions is reported. The spin polarization of cobalt in tunnel junctions with an alumina barrier is positive, but it is negative when the barrier is strontium titanate or cerium lanthanite. The results are ascribed to bonding effects at the transition metal-barrier interface. The influence of the electronic structure of metal-oxide interfaces on the spin polarization raises interesting fundamental problems and opens new ways to optimize the magnetoresistance of tunnel junctions.


Assessment of the variability in influenza A(H1N1) vaccine effectiveness estimates dependent on outcome and methodological approach.
Estimation of Influenza vaccine effectiveness (VE) varies with study design, clinical outcome considered and statistical methodology used. By estimating VE using differing outcomes and statistical methods on the same cohort of individuals the variability in the estimates produced can be better understood. The Pandemic Influenza Primary Care Reporting (PIPeR) cohort of approximately 193,000 individuals was used to estimate pandemic VE in Scotland during season 2009-10. VE results for three outcomes; influenza related consultations, virological confirmed influenza and death were considered. Use of individualised records allowed all models to be adjusted for age, sex, deprivation, risk status relating to chronic illnesses, seasonal vaccination status and a marker of the individual's propensity to consult. For the consultation and death outcomes, VE was calculated by comparing consultation rates in the unvaccinated and vaccinated groups, adjusted for the listed factors, using both Cox and Poisson regression models. For the consultation outcome, the unvaccinated group was split into individuals before vaccination and those never vaccinated to allow for potential differences in the health seeking behaviour of these groups. For the virology outcome estimates were calculated using a generalised additive logistic regression model. All models were adjusted for time. Vaccine effect was demonstrated for the influenza-like illness consultation outcome using the Cox model (VE=49% 95% CI (19%, 67%)) with lower estimates from the model splitting the before and never vaccinated groups (VE=34.2% with 95% CI (-0.5%, 58.9%)). Vaccine effect was also illustrated for overall mortality (VE=40% (95% CI 18%, 56%)) and a virological confirmed subset of symptomatic individuals (VE=60% (95% CI -38%, 89%)). This study illustrates positive point estimates of Influenza VE across methodology and outcome for a single cohort of individuals during season 2009-10. Understanding of potential differences between approaches aids interpretation of VE results in future seasons.


A nutrition curriculum for health education: its effect on students' knowledge, attitude, and behavior.
The objective of the study was to determine the effect of nutrition instruction, using the curriculum guides, Nutrition In A Changing World, A Curriculum for Junior High Health, and A Curriculum for Senior High Health, on improving the nutrition knowledge, selected food/nutrition attitudes, and dietary behavior of students enrolled in secondary level health courses. Three groups of students were utilized including one experimental and two control groups at each level (junior high and senior high). The experimental group was pretested, taught the nutrition curriculum, and posttested. One control group was posttested only to measure the effect of the pretest on posttest performance. A second control group was pretested and posttested. Neither control group received nutrition instruction until after the study was completed. The three instruments used to collect data were a nutrition knowledge test, a food/nutrition attitude instrument, and a food frequency form. The results indicate that, at all grade levels, the experimental group had significantly improved knowledge scores. Little change in attitude scale scores was noted in grades seven and eight, while ninth grade experimental students scored significantly higher on the posttest for all attitude scales. Little improvement was seen in the posttest food frequency scores.


Exogenous administration of vascular endothelial growth factor prior to human respiratory syncytial virus a2 infection reduces pulmonary pathology in neonatal lambs and alters epithelial innate immune responses.
Human respiratory syncytial virus (RSV) affects thousands of children every year. Vascular endothelial growth factor (VEGF) is a regulator of vasculogenesis, pulmonary maturation, and immunity. In order to test the extent to which VEGF may alter RSV infection, 4 groups of lambs received either human recombinant VEGF (rhVEGF) or phosphate-buffered saline (PBS) pretreatment followed by inoculation with human RSV strain A2 or sterile medium. Lambs in each group were sacrificed at 2, 4, and 6 days post infection. Expression of surfactant protein-A (SP-A), surfactant protein-D (SP-D), sheep β-defensin-1 (SBD-1), tumor necrosis factor α (TNFα), interleukin (IL)-6, IL-8, interferon β, and endogenous VEGF were measured to determine effect of rhVEGF pretreatment. RSV lambs pretreated with rhVEGF had reduced viral mRNA and decreased pulmonary pathology at day 6. Pretreatment with rhVEGF increased mRNA expression of SP-A, SBD-1, and TNFα, with alteration of expression in RSV lambs. Endogenous VEGF mRNA levels were increased at day 2 regardless of pretreatment. Pretreatment with rhVEGF increased pulmonary cellular proliferation in RSV lambs at day 4 post infection. Overall, these results suggest that pretreatment with rhVEGF protein may have therapeutic potential to decrease RSV viral load, decrease pulmonary lesion severity, and alter both epithelial innate immune responses and epithelial cell proliferation.


In vivo sucrose stimulation of colour change in citrus fruit epicarps: Interactions between nutritional and hormonal signals.
During ripening, citrus fruit-peel undergoes 'colour break', a process characterized by the conversion of chloroplast to chromoplast. The process involves the progressive loss of chlorophylls and the gain of carotenoids, changing peel colour from green to orange. In the present work, the in vivo and in vitro effects of supplemented nutrients (sucrose and nitrogen) and phytohormones (gibberellins [GA] and ethylene) on colour change in fruit epicarp of Satsuma mandarin (Citrus unshiu (Mak.) Marc., cv. Okitsu), were studied. The rate of colour break was correlated positively with sucrose content and negatively with nitrogen content. The removal of leaves blocked natural sucrose build-up and nitrogen reduction in the peel. Defoliation also inhibited chlorophyll disappearance and carotenoid accumulation, thereby preventing colour break. In vivo sucrose supplementation promoted sucrose accumulation and advanced colour break. In both in vivo and in vitro experiments, colour change promoted by sucrose was unaffected by ethylene but delayed by GA3. In non-supplemented plants, ethylene accelerated colour break while GA3 had no detectable effects. Ethylene inhibitors effectively counteracted the sucrose effects on colour change. Collectively, these results suggest that the chloroplast to chromoplast conversion in citrus fruit epicarps is stimulated by sucrose accumulation. The sugar regulation appears to operate via ethylene, whereas GA may act as a repressor of the sucrose-ethylene stimulation.


Dynamics and spatial organization of Kv1.3 at the immunological synapse of human CD4+ T cells.
Formation of the immunological synapse (IS) is a key event during initiation of an adaptive immune response to a specific antigen. During this process, a T cell and an antigen presenting cell form a stable contact that allows the T cell to integrate both internal and external stimuli in order to decide whether to activate. The threshold for T cell activation depends on the strength and frequency of the calcium (Ca2+) signaling induced by antigen recognition, and it must be tightly regulated to avoid undesired harm to healthy cells. Potassium (K+) channels are recruited to the IS to maintain the negative membrane potential required to sustain Ca2+ entry. However, the precise localization of K+ channels within the IS remains unknown. Here, we visualized the dynamic subsynaptic distribution of Kv1.3, the main voltage-gated potassium channel in human T cells. Upon T cell receptor engagement, Kv1.3 polarized toward the synaptic cleft and diffused throughout the F-actin rich distal compartment of the synaptic interface-an effect enhanced by CD2-CD58 corolla formation. As the synapse matured, Kv1.3 clusters were internalized at the center of the IS and released in extracellular vesicles. We propose a model in which specific distribution of Kv1.3 within the synapse indirectly regulates the channel function and that this process is limited through Kv1.3 internalization and release in extracellular vesicles.


Poorly differentiated synovial sarcoma of the vagina: a case report and a clinical literature review.
Synovial sarcomas (SS) account for 5-10% of soft-tissue sarcomas and typically arise in the para-articular regions of adolescents and young adults. Nonetheless, SS can occasionally occur in other regions of the body. Here, we present a first clinical literature report of a patient with an SS arising from the vaginal wall. A 40-year-old patient who presented a necrotic polypoid lesion, measuring 50 mm and extending from the external urethral meatus to the middle part of the anterior vaginal wall. The biopsy showed a poorly differentiated SS with abundant necrosis and a SYT-SSX1 mutation. A staging CT scan was negative for distant metastases. The patient, prior to the radical surgery, received neoadjuvant chemotherapy (ifosfamide and epirubicin) for three cycles. She underwent post-operative external radiotherapy and brachytherapy (50 Gy) due to close margins (<1 mm) in the pathologic specimen. She relapsed 11 and 16 months later with lung metastases, which, both times, were successfully removed by surgical resection. At 24 months from diagnosis, the patient is alive without further evidence of disease. In summary, in the presence of unfavourable prognostic factors, neoadjuvant chemotherapy could be the primary approach to reduce the tumour size and the risk of distant micro-metastases allowing a less aggressive radical surgery if the tumour is located in a non-extremity site. Hence, a multidisciplinary approach, if not influencing overall survival and disease-free survival, may improve the quality of life. In fact, in our patient we obtained a complete clinical control in the pelvis, avoiding pelvic exenteration with neoadjuvant chemotherapy.


Social influences normalize gambling-related harm among higher risk gamblers.
Social influences are key drivers of gambling, and can begin in youth through parental modeling and facilitation. Over time, social influence from friends and colleagues also becomes important. Social network analysis provides a method to measure the combined nature of these social influences. This study aimed to compare social influences across gambling risk groups, by examining key characteristics of the social networks, among Australian adults. A total of 784 respondents (egos) reported their demographics, gambling behavior and gambling risk, as well as those of the 20 most influential people in their lives (alters). Egos also reported the strength of the connection between themselves and each of their alters, and between each pair of alters. Data were analyzed using egocentric social network analysis approaches. Egos in higher risk groups reported more alters who gamble, including a higher proportion experiencing gambling-related harm. Relationship strength indicated that egos in higher risk groups tended to feel closer to their alters, regardless of whether the alter gambles or not. Network density (interconnectedness between alters) was greater for egos in higher risk groups. The findings indicate that both gambling behavior and gambling-related harm are normalized through social connections. Greater interconnectedness in the networks of higher risk gamblers indicates difficulties in reducing or removing these influences. The findings indicate limitations of individualised interventions, and instead highlight the important role of changing norms within society, which can be transmitted throughout these networks.


A higher-level phylogenetic classification of the Fungi.
A comprehensive phylogenetic classification of the kingdom Fungi is proposed, with reference to recent molecular phylogenetic analyses, and with input from diverse members of the fungal taxonomic community. The classification includes 195 taxa, down to the level of order, of which 16 are described or validated here: Dikarya subkingdom nov.; Chytridiomycota, Neocallimastigomycota phyla nov.; Monoblepharidomycetes, Neocallimastigomycetes class. nov.; Eurotiomycetidae, Lecanoromycetidae, Mycocaliciomycetidae subclass. nov.; Acarosporales, Corticiales, Baeomycetales, Candelariales, Gloeophyllales, Melanosporales, Trechisporales, Umbilicariales ords. nov. The clade containing Ascomycota and Basidiomycota is classified as subkingdom Dikarya, reflecting the putative synapomorphy of dikaryotic hyphae. The most dramatic shifts in the classification relative to previous works concern the groups that have traditionally been included in the Chytridiomycota and Zygomycota. The Chytridiomycota is retained in a restricted sense, with Blastocladiomycota and Neocallimastigomycota representing segregate phyla of flagellated Fungi. Taxa traditionally placed in Zygomycota are distributed among Glomeromycota and several subphyla incertae sedis, including Mucoromycotina, Entomophthoromycotina, Kickxellomycotina, and Zoopagomycotina. Microsporidia are included in the Fungi, but no further subdivision of the group is proposed. Several genera of 'basal' Fungi of uncertain position are not placed in any higher taxa, including Basidiobolus, Caulochytrium, Olpidium, and Rozella.


Cost-effectiveness of interventions promoting physical activity.
Sedentary and inactive lifestyle continues to increase and is associated with a substantial economic burden in most industrialised countries. To implement effective physical activity interventions on a broad population basis, their cost-effectiveness needs to be evaluated. To evaluate the cost-effectiveness of physical activity interventions targeted at healthy adults and to identify cost-effective intervention components. Systematic review. Methods and The search strategy in electronic databases identified relevant literature published until June 2008. We included studies investigating the cost-effectiveness of interventions aiming to promote physical activity behaviour in healthy adults. Two researchers independently assessed publications according to predefined inclusion criteria and with regard to methodological quality. Study characteristics and predefined outcome measures were extracted and costs per participant to become sufficiently active were compared between interventions. Out of 6543 identified publications, eight studies investigating 11 intervention strategies met the inclusion criteria. There was substantial heterogeneity in study quality, intervention strategies and intervention effects. Behavioural interventions were able to promote physical activity, with participants meeting recommended levels of physical activity, for about 800 Euros per year. Environmental interventions and interventions targeted at general practitioners seemed to have the potential to be substantially more cost-effective. There was evidence that current physical activity intervention strategies can be a cost-effective means of resource allocation. But, despite the growing literature on physical activity promotion, appropriate cost-effectiveness analyses are rare and the generalisability of presented findings is limited. Further research is warranted to investigate the cost-effectiveness of behavioural and environmental intervention strategies.


The orbital period of the ultraluminous x-ray source in M82.
The ultraluminous x-ray source (ULX) in the galaxy M82 has been identified as a possible intermediate-mass black hole formed in stellar collisions in the super star cluster MGG 11. The x-ray flux from M82 is modulated, with a peak-to-peak amplitude corresponding to an isotropic luminosity of 2.4 _ 1040 erg s-1 in M82 and a period of 62.0 +/- 2.5 days, which we interpret as the orbital period of the ULX binary. This orbital period implies that the mass-donor star must be a giant or supergiant. Large mass-transfer rates, sufficient to fuel the ULX, are expected for a giant-phase mass donor in an x-ray binary. The giant phase has a short lifetime, indicating that we see the ULX in M82 in a brief and unusual period of its evolution.


NovaMedTech - a regional program for supporting new medical technologies in personalized health care.
NovaMedTech is an initiative funded from EU structural funds for supporting new medical technologies for personalized health care. It aims at bringing these technologies into clinical use and to the health care market. The program has participants from health care, industry and academia in East middle Sweden. The first three year period of the program was successful in terms of product concepts tried clinically, and number of products brought to a commercialization phase. Further, the program has led to a large number of scientific publications. Among projects supported, we can mention: Intelligent sensor networks; A digital pen to collect medical information about health status from patients; A web-based intelligent stethoscope; Methodologies to measure local blood flow and nutrition using optical techniques; Blood flow assessment from ankle pressure measurements; Technologies for pressure ulcer prevention; An IR thermometer for improved accuracy; A technique that identifies individuals prone to commit suicide among depressed patients; Detection of infectious disease using an electronic nose; Identification of the lactate threshold from breath; Obesity measurements using special software and MR camera; and An optical probe guided tumor resection. During the present three years period emphasis will be on entrepreneurial activities supporting the commercialization and bringing products to the market.


Content Word Production during Discourse in Aphasia: Deficits in Word Quantity, Not Lexical-Semantic Complexity.
Although limited and reduced connected speech production is one, if not the most, prominent feature of aphasia, few studies have examined the properties of content words produced during discourse in aphasia, in comparison to the many investigations of single-word production. In this study, we used a distributional analysis approach to investigate the properties of content word production during discourse by 46 participants spanning a wide range of chronic poststroke aphasia and 20 neurotypical adults, using different stimuli that elicited three discourse genres (descriptive, narrative, and procedural). Initially, we inspected the discourse data with respect to the quantity of production, lexical-semantic diversity, and psycholinguistic features (frequency and imageability) of content words. Subsequently, we created a "lexical-semantic landscape," which is sensitive to subtle changes and allowed us to evaluate the pattern of changes in discourse production across groups. Relative to neurotypical adults, all persons with aphasia (both fluent and nonfluent) showed significant reduction in the quantity and diversity of production, but the lexical-semantic complexity of word production directly mirrored neurotypical performance. Specifically, persons with aphasia produced the same rate of nouns/verbs, and their discourse samples covered the full range of word frequency and imageability, albeit with reduced word quantity. These findings provide novel evidence that, unlike in other disorders (e.g., semantic dementia), discourse production in poststroke aphasia has relatively preserved lexical-semantic complexity but demonstrates significantly compromised quantity of content word production. Voxel-wise lesion-symptom mapping using both univariate and multivariate approaches revealed left frontal regions particularly the pars opercularis, insular cortex, and central and frontal opercular cortices supporting word retrieval during connected speech, irrespective of their word class or lexical-semantic complexity.


A cross-sectional study of fatigue and sleep quality before and after kidney transplantation.
Fatigue and sleep disturbances are common problems for adults with chronic kidney disease or end-stage renal disease. However, these issues have not been examined much in the context of kidney transplantation (KTx). This study characterizes these outcomes in the KTx population and examines their association with psychological functioning and quality of life (QOL). A cross-sectional cohort of 100 wait-listed pre-KTx and 100 post-KTx patients at one transplant center in the United States completed validated fatigue, sleep, mood, and QOL questionnaires, and their medical records were reviewed. Pre-KTx patients had higher levels of fatigue frequency, fatigue severity, and fatigue disruptiveness than post-KTx patients. Also, pre-KTx patients had more difficulty with sleep quality, latency, duration, efficiency, and disturbance and were more likely to have "poor" sleep quality compared with post-KTx patients. Multivariate predictors of high fatigue severity for both pre- and post-KTx patients were high body mass index (BMI), poor sleep quality, and mood disturbance, while poor sleep quality was predicted by high BMI and mood disturbance. Most sociodemographic and clinical parameters were not associated with fatigue severity or sleep disturbance. Fatigue and sleep disturbances are common before and after KTx, and study findings have important implications for their assessment and management.


Dysplasia in short-segment Barrett's esophagus: a prospective 3-year follow-up.
Short segments of intestinal metaplasia in the distal esophagus are being recognized with increasing frequency. Both long and short segments of Barrett's esophagus can progress to dysplasia and cancer. However, the risk of short-segment Barrett's esophagus (SSBE) for the development of dysplasia and adenocarcinoma of the esophagus is not yet known. Our purpose, therefore, was to determine the frequency with which dysplasia occurs in patients with SSBE. Patients with SSBE were followed prospectively for the development of dysplasia. SSBE was defined as <3 cm of Barrett's-appearing epithelium above the gastroesophageal junction at endoscopy, with intestinal metaplasia on biopsy as documented by alcian blue stain at pH 2.5 on at least two endoscopic biopsies 6 months apart. Patients had interval upper endoscopy with systematic biopsy of the Barrett's segment. Fifty-nine SSBE patients were identified. The mean length of Barrett's mucosa was 1.5 +/- 0.1 cm; the mean age of the patients was 63.1 +/- 1.3 yr. Five patients had low-grade dysplasia (LGD) at initial endoscopy, for a prevalence of 8.5%; none had high grade dysplasia (HGD). Thirty-two patients had follow-up endoscopy over a mean period of 36.9 +/- 5.4 months. Five of these patients developed dysplasia on follow-up, three with LGD and two with HGD, the incidence of any dysplasia being 5.7% per year. One patient with HGD that developed during surveillance progressed to adenocarcinoma of the esophagus over a 2-yr period. The other patient with HGD had LGD on follow-up endoscopy. Six patients with initial LGD had no evidence of dysplasia on follow-up. The prevalence of dysplasia was 8.5% with an incidence of 5.7% per year in this group of SSBE patients, followed prospectively. Although dysplastic changes may not be identified on follow-up examination, some patients progress to adenocarcinoma. Therefore, we recommend surveillance endoscopy and biopsy in patients with SSBE just as in those with long-segment Barrett's esophagus.


Interactive level-of-detail selection using image-based quality metric for large volume visualization.
For large volume visualization, an image-based quality metric is difficult to incorporate for level-of-detail selection and rendering without sacrificing the interactivity. This is because it is usually time-consuming to update view-dependent information as well as to adjust to transfer function changes. In this paper, we introduce an image-based level-of-detail selection algorithm for interactive visualization of large volumetric data. The design of our quality metric is based on an efficient way to evaluate the contribution of multiresolution data blocks to the final image. To ensure real-time update of the quality metric and interactive level-of-detail decisions, we propose a summary table scheme in response to runtime transfer function changes and a GPU-based solution for visibility estimation. Experimental results on large scientific and medical data sets demonstrate the effectiveness and efficiency of our algorithm.


Navigating the cultural geography of indigenous peoples' attitude toward genetic research: the Ohana (family) heart project.
Little is known about the burden of heart failure among indigenous populations, including Native Hawaiians (NH). Recent concerns about genetic research in the NH community resonate with similar concerns raised by American Indian, Alaskan Native and Canadian First Nations communities and have raised questions about the best way to proceed with studies involving biological specimens. To help us plan a study to investigate disparities in heart failure incidence and outcomes in a NH community, we performed a qualitative study to examine the community's expectations for heart failure research that includes the collection of biological specimens. Eighty-five NH with a personal or family history of heart failure, who lived in a geographically isolated community in the state of Hawai'i participated in 1 of 16 semi-structured interviews. Interviews were conducted in a standard manner, with open-ended questions designed to explore their expectations for a heart failure research study that included the collection of biological specimens. Interviews were analyzed thematically through iterative readings and coding. four key themes regarding heart failure research with the use of biological specimens characterized their expectations: (a) Need to foster trust between investigator and community; (b) Establish a partnership with the community to identify needs and goals; (c) Need for mutual benefit to investigator and community; (d) Identification of a key voice to represent the community. Participants expressed strong support for research. However, the strength of that support was directly related to the strength of the relationship between the research team and the community. The collection of biological specimens for genetic analyses was not an explicit concern or barrier per se. It appears feasible to conduct a heart failure research study that includes the collection of biological samples. However, success will likely require addressing the community's expectations, including the need for a long-term partnership built on trust and mutual benefit, and a key voice to represent the community.


Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells.
The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein.


[Actual management of pregnancies at risk for fetal anemia].
To evaluate the utilisation measurements of peak systolic velocities in the middle cerebral artery (MCA-PSV) to predict the degree of fetal anemia and to find out whether implementation of MCA-PSV into management of pregnancies at risk for fetal anemia enable to reduce the number of invasive procedures. A prospective study. Department of Obstetrics and Gynecology, Department of Medical Genetics and Fetal Medicine, Neonatology Department, University Hospital, Olomouc. In 81 pregnancies at risk for fetal anemia MCA-PSV had been assessed and fetal blood sampling for measurement of hemoglobin concentration was obtained subsequently, either by cordocentesis or at delivery. The values of MCA-PSV and hemoglobin concentration were expressed as multiples of median (MoM). Anemia was defined as mild (hemoglobin <0.84 MoM) for a given gestational age, moderate (hemoglobin <0.65 MoM), and severe (hemoglobin <0.55 MoM). The number of cordocenteses performed in previous conventional management of pregnacies at risk for fetal anemia was compared with management by Doppler measurement of MCA-PSV. 313 examinations were performed at 17-38 week's gestation. An MCA-PSV >1.5 MoM detected 100% of severly anemic fetuses with a hemoglobin concentration <0,65 MoM that required invasive intervention. In 27 cases a cordocentesis was performed and intrauterine blood transfusion was given alternatively. Remaining fetuses did not require invasive intrauterine intervention and no or mild hemolytic anemia and hyperbilirubinemia were diagnosed after delivery. Overall sensitivity to detect moderate to severe anemia (hemoglobin <0.65 MoM for a given gestational age) was 100%. Specificity was 92%, positive predictive value was 60% and negative predictive value was 100%. One false positive case was identified after 35 weeks. In 2002 at least one cordocentesis was performed in all pregnancies at risk for fetal anemia 100%, in 2003 78%, in 2004 20% and in 2005 20%. At least one cordocentesis with intrauterine blood transfusion was required by only 24% of all fetuses at risk for fetal anemia. The other fetuses 76% (34/45) didn't require intrauterine transfusion. Middle cerebral artery peak systolic velocity is a highly sensitive non-invasive means for determining the degree of fetal anemia and implementation of MCA-PSV into management of pregnancies at risk for fetal anemia enable to reduce the number of invasive procedures. This parameter should not yet be considered the global standard of care for diagnosis of fetal anemia because incorrect use by an unexperienced operator may cause more harm than good. However, if there is a reasonably close medical center with sonographers tranined to assess the MCA-PSV, patients at risk for fetal anemia should be reffered to this center.


3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors.
The chromatin remodeling amine oxidase lysine-specific demethylase 1 (LSD1) has become an attractive target for the design of specific inhibitors with therapeutic potential. We, and others, have described LSD1 inhibitors that have potential as antitumor agents. Many of the currently known LSD1 inhibitors are poor drug candidates, or are structurally based on the tranylcypromine backbone, thus increasing the potential for off-target effects mediated by other amine oxidases. We now describe a series of potent LSD1 inhibitors based on a novel 1,2,4-triazole scaffold; these inhibitors show a high degree of specificity for LSD1 in vitro, and cause increases in cellular histone 3 dimethyllysine 4 (H3K4me2), a gene transcription activating mark. Importantly, these inhibitors are not toxic to mammalian cells in vitro, and thus they may show utility in the treatment of epigenetically-based diseases where cell death is not a desired endpoint Figure 1. Structures of LSD1 inhibitors 1, verlindamycin 2, (bis)thioureas 3, amidoxime 4, cyclic peptide 5, N3-(2-chloro-6-phenoxybenzyl)-4H-1,2,4-triazole-3,5-diamine 6 and N3,N5-bis(2-methoxybenzyl)-1H-1,2,4-triazole-3,5-diamine 7.


Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee.
Primary immunodeficiency diseases (PIDs) are a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. More than 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic,immunologic, and clinical features of PID has prompted the need for their classification, with the ultimate goal of facilitating diagnosis and treatment. To serve this goal, an international committee of experts has met every 2 years since 1970. In its last meeting in Jackson Hole, Wyo, after 3 days of intense scientific presentations and discussions, the committee has updated the classification of PID, as reported in this article.


Enterohemorrhagic Escherichia coli as causes of hemolytic uremic syndrome in the Czech Republic.
Enterohemorrhagic Escherichia coli (EHEC) cause diarrhea-associated hemolytic uremic syndrome (D+ HUS) worldwide, but no systematic study of EHEC as the causative agents of HUS was performed in the Czech Republic. We analyzed stools of all patients with D+ HUS in the Czech Republic between 1998 and 2012 for evidence of EHEC infection. We determined virulence profiles, phenotypes, antimicrobial susceptibilities and phylogeny of the EHEC isolates. Virulence loci were identified using PCR, phenotypes and antimicrobial susceptibilities were determined using standard procedures, and phylogeny was assessed using multilocus sequence typing. During the 15-year period, EHEC were isolated from stools of 39 (69.4%) of 56 patients. The strains belonged to serotypes [fliC types] O157:H7/NM[fliC(H7)] (50% of which were sorbitol-fermenting; SF), O26:H11/NM[fliC(H11)], O55:NM[fliC(H7)], O111:NM[fliC(H8)], O145:H28[fliC(H28)], O172:NM[fliC(H25)], and Orough:NM[fliC(H250]. O26:H11/NM[fliC(H11)] was the most common serotype associated with HUS (41% isolates). Five stx genotypes were identified, the most frequent being stx(2a) (71.1% isolates). Most strains contained EHEC-hlyA encoding EHEC hemolysin, and a subset (all SF O157:NM and one O157:H7) harbored cdt-V encoding cytolethal distending toxin. espPα encoding serine protease EspPα was found in EHEC O157:H7, O26:H11/NM, and O145:H28, whereas O172:NM and Orough:NM strains contained espPγ. All isolates contained eae encoding adhesin intimin, which belonged to subtypes β (O26), γ (O55, O145, O157), γ2/θ (O111), and ε (O172, Orough). Loci encoding other adhesins (efa1, lpfA(O26), lpfA(O157OI-141), lpfA(O157OI-154), iha) were usually associated with particular serotypes. Phylogenetic analysis demonstrated nine sequence types (STs) which correlated with serotypes. Of these, two STs (ST660 and ST1595) were not found in HUS-associated EHEC before. EHEC strains, including O157:H7 and non-O157:H7, are frequent causes of D+ HUS in the Czech Republic. Identification of unusual EHEC serotypes/STs causing HUS calls for establishment of an European collection of HUS-associated EHEC, enabling to study properties and evolution of these important pathogens.


Attention bias toward threat is associated with exaggerated fear expression and impaired extinction in PTSD.
Post-traumatic stress disorder (PTSD) develops in a minority of traumatized individuals. Attention biases to threat and abnormalities in fear learning and extinction are processes likely to play a critical role in the creation and/or maintenance of PTSD symptomatology. However, the relationship between these processes has not been established, particularly in highly traumatized populations; understanding their interaction can help inform neural network models and treatments for PTSD. Attention biases were measured using a dot probe task modified for use with our population; task stimuli included photographs of angry facial expressions, which are emotionally salient threat signals. A fear-potentiated startle paradigm was employed to measure atypical physiological response during acquisition and extinction phases of fear learning. These measures were administered to a sample of 64 minority (largely African American), highly traumatized individuals with and without PTSD. Participants with PTSD demonstrated attention biases toward threat; this attentional style was associated with exaggerated startle response during fear learning and early and middle phases of extinction, even after accounting for the effects of trauma exposure. Our findings indicate that an attentional bias toward threat is associated with abnormalities in 'fear load' in PTSD, providing seminal evidence for an interaction between these two processes. Future research combining these behavioral and psychophysiological techniques with neuroimaging will be useful toward addressing how one process may modulate the other and understanding whether these phenomena are manifestations of dysfunction within a shared neural network. Ultimately, this may serve to inform PTSD treatments specifically designed to correct these atypical processes.


Equitable resourcing of primary health care in remote communities in Australia's Northern Territory: a pilot study.
Improved Primary Health Care (PHC) utilisation is central to reducing the unacceptable morbidity and mortality rates characterising populations living in remote communities. Despite poorer health, significant inequity characterises the funding of PHC services in Australia's most remote areas. This pilot study sought to ascertain what funding is required to ensure equitable access to sustainable, high quality primary health care irrespective of geographical remoteness of communities. High performing remote Primary Health Care (PHC) services were selected using improvement measures from the Australian Primary Care Collaboratives Program and validated by health experts. Eleven PHC services provided data relating to the types of services provided, level of service utilisation, human resources, operating and capital expenses. A further four services that provide visiting PHC to remote communities provided information on the level and cost of these services. Demographic data for service catchment areas (including estimated resident population, age, Indigenous status, English spoken at home and workforce participation) were obtained from the Australian Bureau of Statistics 2011 census. Formal statistical inference (p-values) were derived in the linear regression via the nonparametric bootstrap. A direct linear relationship was observed between the total cost of resident PHC services and population, while cost per capita decreased with increasing population. Services in smaller communities had a higher number of nursing staff per 1000 residents and provided more consultations per capita than those in larger communities. The number of days of visiting services received by a community each year also increased with population. A linear regression with bootstrapped statistical inference predicted a significant regression equation where the cost of resident services per annum is equal to $1,251,893.92 + ($1698.83 x population) and the cost of resident and visiting services is equal to $1,378,870.85 + ($2600.00 x population). The research findings provide empirical evidence based on real costs to guide funding for remote PHC services that takes into account the safety and equity requirements for a minimum viable service. This method can be used as a transparent, coordinated approach to ensure the equitable delivery of sustainable, high quality PHC in remote communities. This will in turn contribute to improved health outcomes.


Bacterial recognition by PGRP-SA and downstream signalling by Toll/DIF sustain commensal gut bacteria in Drosophila.
The gut sets the immune and metabolic parameters for the survival of commensal bacteria. We report that in Drosophila, deficiency in bacterial recognition upstream of Toll/NF-κB signalling resulted in reduced density and diversity of gut bacteria. Translational regulation factor 4E-BP, a transcriptional target of Toll/NF-κB, mediated this host-bacteriome interaction. In healthy flies, Toll activated 4E-BP, which enabled fat catabolism, which resulted in sustaining of the bacteriome. The presence of gut bacteria kept Toll signalling activity thus ensuring the feedback loop of their own preservation. When Toll activity was absent, TOR-mediated suppression of 4E-BP made fat resources inaccessible and this correlated with loss of intestinal bacterial density. This could be overcome by genetic or pharmacological inhibition of TOR, which restored bacterial density. Our results give insights into how an animal integrates immune sensing and metabolism to maintain indigenous bacteria in a healthy gut.


Molecular cloning of cDNAs encoding two pigment-dispersing hormones and two corresponding genes from the kuruma prawn (Penaeus japonicus).
Pigment-dispersing hormone (PDH) controls pigment dispersion in chromatophores. In this study cDNAs encoding 2 PDH precursors of the kuruma prawn (Penaeus japonicus) (Pej-PDH-I and Pej-PDH-II) were cloned. Both precursors consisted of a signal peptide, a PDH-precursor-related peptide (PPRP), and PDH. The PPRPs were homologous to those in other crustacean species, but not to those of pigment-dispersing factors (PDFs) in insects, which were members of the PDH/PDF family. Two corresponding genes were also cloned. Sequence analyses revealed that the Pej-PDH-I gene had 3 exons separated by 2 introns, while the Pej-PDH-II gene had 2 exons separated by 1 intron. The exon/intron organizations in the PDH genes were different from that of the Drosophila melanogaster PDF gene, which is intronless. Analyses by reverse transcription polymerase chain reaction demonstrated that both transcripts existed only in the eyestalk, but not in the brain, thoracic ganglia, abdominal ganglia, hindgut, or hepatopancreas.


Palinacousis: a case report.
Palinacousis (auditory perseveration) is a rarely reported symptom of temporal lobe dysfunction. We describe a new case. A 50-year-old woman presented with nausea, vomiting, and global dysphasia, followed by two generalized seizures. Examination was otherwise normal, and computed tomography showed a small area of enhancement near the left sylvian fissure; there was a left temporal focus on the electroencephalogram. Treatment with phenytoin was instituted, and speech improved, with residual fluent dysphasia. Three days postictally, the patient complained of "echoing voices" in her right ear. Words or fragments of sentences recently uttered by the patient or others were perceived to recur unaltered for minutes to hours. Sounds other than speech were also affected. One week later the voices had disappeared, but a ticking sound was present; this also faded subsequently. The palinacousis never recurred; the patient was later found to have a Grade IV astrocytoma of the left temporal lobe, which caused her demise 8 months later. The features of this case are similar to those previously reported and favor an epileptic etiology. Palinacousis should be recognized as a sign of organic temporal lobe disease and not confused with manifestations of psychotic illness.


Development during adolescence of the neural processing of social emotion.
In this fMRI study, we investigated the development between adolescence and adulthood of the neural processing of social emotions. Unlike basic emotions (such as disgust and fear), social emotions (such as guilt and embarrassment) require the representation of another's mental states. Nineteen adolescents (10-18 years) and 10 adults (22-32 years) were scanned while thinking about scenarios featuring either social or basic emotions. In both age groups, the anterior rostral medial prefrontal cortex (MPFC) was activated during social versus basic emotion. However, adolescents activated a lateral part of the MPFC for social versus basic emotions, whereas adults did not. Relative to adolescents, adults showed higher activity in the left temporal pole for social versus basic emotions. These results show that, although the MPFC is activated during social emotion in both adults and adolescents, adolescents recruit anterior (MPFC) regions more than do adults, and adults recruit posterior (temporal) regions more than do adolescents.


The deep subsurface biosphere in igneous ocean crust: frontier habitats for microbiological exploration.
We discuss ridge flank environments in the ocean crust as habitats for subseafloor microbial life. Oceanic ridge flanks, areas far from the magmatic and tectonic influence of seafloor spreading, comprise one of the largest and least explored microbial habitats on the planet. We describe the nature of selected ridge flank crustal environments, and present a framework for delineating a continuum of conditions and processes that are likely to be important for defining subseafloor microbial "provinces." The basis for this framework is three governing conditions that help to determine the nature of subseafloor biomes: crustal age, extent of fluid flow, and thermal state. We present a brief overview of subseafloor conditions, within the context of these three characteristics, for five field sites where microbial studies have been done, are underway, or have been proposed. Technical challenges remain and likely will limit progress in studies of microbial ridge flank ecosystems, which is why it is vital to select and design future studies so as to leverage as much general understanding as possible from work focused at a small number of sites. A characterization framework such that as presented in this paper, perhaps including alternative or additional physical or chemical characteristics, is essential for achieving the greatest benefit from multidisciplinary microbial investigations of oceanic ridge flanks.


Mineralogy influences structure and diversity of bacterial communities associated with geological substrata in a pristine aquifer.
Our understanding of mineralogical influences on subsurface microbial community structure and diversity has been difficult to assess due to difficulties in isolating this variable from others in the subsurface environment. In this study, biofilm coupons were used to isolate specific geological substrata from the surrounding geological matrix during colonization by microorganisms suspended in the surrounding groundwater for an 8-week period. Upon retrieval, the structure and diversity of the microbial community associated with each type of substratum was evaluated using 16S rDNA-based terminal-restriction fragment length polymorphism (T-RFLP). Phylogenetic affiliations of the populations associated with each type of substratum were established based on sequence analysis of near full-length 16S rDNA obtained through construction of a clone library. Hematite, quartz, and saprolite each harbored a community dominated by members of the division Proteobacteria (>67% of community). However, the different substrata selected for different subdivisions of bacteria within the Proteobacteria. After accounting for the influence exerted by substratum type on recovery of DNA from the attached populations, both phylogenetic data and Jaccard and Bray-Curtis similarity indices derived from terminal-restriction fragment (T-RF) profiles suggested a strong mineralogical influence on the structure and composition of the solid phase-associated community. The results suggest that mineralogical heterogeneity influences microbial community structure and diversity in pristine aquifers.


Volatile anesthetics reduce invasion of colorectal cancer cells through down-regulation of matrix metalloproteinase-9.
Invasion of extracellular matrix is a hallmark of malignant tumors. Clamping maneuvers during cancer surgery reduce blood loss, but trigger reperfusion injury (RI). RI increases cancer recurrence in the reperfused organ through up-regulation of matrix metalloproteinase-9 (MMP-9). Interleukin-8 is an important cytokine in RI promoting accumulation of neutrophils, a major source of MMP-9. Volatile anesthetics were demonstrated to reduce RI. We hypothesized that these anesthetics might attenuate MMP-9 up-regulation and consequently tumor cell invasion in RI. Isolated human neutrophils (n = 6) were preconditioned with sevoflurane or desflurane, followed by stimulation with interleukin-8, phorbol myristate acetate, or chemokine CXC-ligand 1 (CXCL1) to differentiate intracellular pathways. MMP-9 release and activity were quantified by enzyme-linked immunosorbent assay and zymography, respectively. CXC-receptor-2 (CXCR2) expression and phosphorylation of extracellular signal-regulated kinases 1/2 were assessed by flow cytometry. The impact of MMP-9 on the invasion of neutrophils and MC-38 colon cancer cells was assessed using Matrigel-coated filters (n = 6). Preconditioning reduced interleukin-8-induced MMP-9-release by 41% (±13, 5%, sevoflurane) and 40% (±13%, desflurane). This was also evident following stimulation of CXCR2 with CXCL1. No impact on phosphorylation of extracellular signal-regulated kinases 1/2 and MMP-9 release was observed with receptor-independent stimulation of protein kinase C with phorbol myristate acetate. Preconditioning reduced transmigration of neutrophils and MC-38 tumor cells to baseline levels. Volatile anesthetics impair neutrophil MMP-9 release and interfere with pathways downstream of CXCR2, but upstream of protein kinase C. Through down-regulation of MMP-9, volatile anesthetics decrease Matrigel breakdown and reduce subsequent migration of cancer cells in vitro.


Radiation-induced hyposuppression of the hypothalamic-pituitary-adrenal axis is associated with alterations of hippocampal corticosteroid receptor expression.
Therapeutic brain irradiation in children can cause a progressive decline in cognitive functions through a diminished capability to learn and memorize. Because of the known involvement of the hippocampus in memory consolidation, this study was aimed at examining the late effects of gamma radiation on hypothalamic-pituitary-adrenal (HPA) axis activity and hippocampal corticosteroid receptor expression in an animal model of cranial radiotherapy. In the late-response phase, the basal and stress-induced corticosterone levels were not affected by radiation, but the suppression of glucocorticoid negative feedback by dexamethasone was attenuated in irradiated rats. Western blot analyses showed that exposure to radiation led to a decrease of cytosolic glucocorticoid receptor (GR) levels and a concomitant elevation of mineralocorticoid receptor (MR). The results obtained were complemented by those of RT-PCR, since the ratio of GR/MR mRNA was also decreased after radiation exposure. Dexamethasone appeared to be much less effective in shifting GR to the nuclear compartment in irradiated rats than in sham-irradiated animals. However, the expression of chaperones that aid GR intracellular trafficking, Hsp90 and Hsp70, remained unaffected. In conclusion, our data suggest that the hallmark of the late response to gamma radiation is a hyposuppressive state of the HPA axis that is associated with a decrease in both the GR/MR ratio and the nuclear accumulation of dexamethasone-activated GR in the hippocampus.


Interferon-gamma and monoclonal antibody 131I-labeled CC49: outcomes in patients with androgen-independent prostate cancer.
To assess the tumor targeting, safety, and efficacy of monoclonal antibody 131I-labeled CC49 in patients with androgen-independent prostate cancer, 16 patients received 75 mCi/m2 of the radiolabeled antibody after 7 days of IFN-gamma pretreatment. Sequential tumor biopsies in three patients showed a median 5-fold (range, 2-6-fold) increase in the proportion of cells staining positively for the TAG-72 antigen, whereas one showed a decrease in staining. Fourteen patients received 131I-labeled CC49, whereas 2 showed a disease-related decrease in performance status, precluding antibody treatment. The antibody localized to sites of metastatic androgen-independent prostate cancer in 86% (12 of 14; 95% confidence interval, 57-95%) of cases. Both osseous and extraosseous sites were visualized, and in six (42%) patients, more areas were visible when the radioimmunoconjugate was used than were apparent when conventional scanning techniques were used. The localization of the conjugate in the marrow cavity was usually a site not visualized by the radionuclide bone scan, in which the isotope localizes primarily to the tumor-bone interface. The dose-limiting toxicity was thrombocytopenia because five (36%) patients showed grade IV and seven (50%) showed grade III effects. In addition, six (42%) patients, four of whom were hospitalized, showed a flare in baseline pain, and four showed a decrease in pain. No patient showed a >50% decline in prostate-specific antigen, although radionuclide bone scans remained stable in four cases for a median of 4 months. The results are consistent with dosimetry estimates showing that the delivered dose to tumor was subtherapeutic and suggest that approaches that exclusively target the bone tumor interface or the marrow stroma may be unable to completely eradicate disease in the marrow cavity. For CC49, improving outcomes would require repetitive dosing, which was precluded by the rapid development of a human antimouse antibody response.


Asymptomatic solitary papilloma of the bronchus: review of occurrence in Japan.
A case of solitary papilloma of the bronchus is described, and 15 other cases occurring in Japan are reviewed. A 57 year old asymptomatic male was referred to our hospital because many squamous metaplastic cells with moderate atypia were observed in sputum cytology, twice in 3 months. The chest X-ray showed no abnormal findings. Endoscopic examination revealed a polypoid tumour at the bifurcation of the right B6a and B6b. The tumour was removed completely by endoscopic biopsy, and histological findings showed squamous papilloma. There has been no evidence of recurrence for 3 yrs. We are not aware of a previously reported case of bronchial papilloma without symptoms or abnormal shadow on chest X-ray. Considering the fact that malignant change was reported in only one case in Japan, and that there is a possibility of cancer subsequently developing at another location in the lung which might also require resection, lobectomy should be avoided if the tumour can be removed completely through endoscopy. If the lesion is limited to a small area in the bronchus, conservative treatment such as photodynamic therapy and/or yttrium aluminium garnet (YAG) laser vaporization might be sufficient to obtain a complete cure.


Temperature alters the shape of predator-prey cycles through effects on underlying mechanisms.
Predicting the effects of climate warming on the dynamics of ecological systems requires understanding how temperature influences birth rates, death rates and the strength of species interactions. The temperature dependance of these processes-which are the underlying mechanisms of ecological dynamics-is often thought to be exponential or unimodal, generally supported by short-term experiments. However, ecological dynamics unfold over many generations. Our goal was to empirically document shifts in predator-prey cycles over the full range of temperatures that can possibly support a predator-prey system and then to uncover the effect of temperature on the underlying mechanisms driving those changes. We measured the population dynamics of the Didinium-Paramecium predator-prey system across a wide range of temperatures to reveal systematic changes in the dynamics of the system. We then used ordinary differential equation fitting to estimate parameters of a model describing the dynamics, and used these estimates to assess the long-term temperature dependance of all the underlying mechanisms. We found that predator-prey cycles shrank in state space from colder to hotter temperatures and that both cycle period and amplitude varied with temperature. Model parameters showed mostly unimodal responses to temperature, with one parameter (predator mortality) increasing monotonically with temperature and one parameter (predator conversion efficiency) invariant with temperature. Our results indicate that temperature can have profound, systematic effects on ecological dynamics, and these can arise through diverse and simultaneous changes in multiple underlying mechanisms. Predicting the effects of temperature on ecological dynamics may require additional investigation into how the underlying drivers of population dynamics respond to temperature beyond a short-term, acute response.


Effect of pH Test-Strip Characteristics on Accuracy of Readings.
Little is known about characteristics of colorimetric pH test strips that are most likely to be associated with accurate interpretations in clinical situations. To compare the accuracy of 4 pH test strips with varying characteristics (ie, multiple vs single colorimetric squares per calibration, and differing calibration units [1.0 vs 0.5]). A convenience sample of 100 upper-level nursing students with normal color vision was recruited to evaluate the accuracy of the test strips. Six buffer solutions (pH range, 3.0 to 6.0) were used during the testing procedure. Each of the 100 participants performed 20 pH tests in random order, providing a total of 2000 readings. The sensitivity and specificity of each test strip was computed. In addition, the degree to which the test strips under- or overestimated the pH values was analyzed using descriptive statistics. Our criterion for correct readings was an exact match with the pH buffer solution being evaluated. Although none of the test strips evaluated in our study was 100% accurate at all of the measured pH values, those with multiple squares per pH calibration were clearly superior overall to those with a single test square. Test strips with multiple squares per calibration were associated with greater overall accuracy than test strips with a single square per calibration. However, because variable degrees of error were observed in all of the test strips, use of a pH meter is recommended when precise readings are crucial.


Lactic acidosis associated with stavudine administration: a report of five cases.
Type "B" lactic acidosis has been described in patients receiving the nucleoside analogs zidovudine, didanosine, and fialuridine. Lactic acidosis has also been described in 4 patients receiving combination therapy with stavudine and lamivudine. We describe the development of chronic type "B" lactic acidosis in 3 patients receiving stavudine as a single agent and in 2 patients receiving combination therapy with stavudine and either lamivudine or delavirdine, a nonnucleoside analog. All patients presented with abdominal pain, vomiting, and hepatic steatosis. Other signs of mitochondrial toxicity included pancreatitis and myopathy (2 cases). The mean duration of stavudine therapy was 9.4 months, and the mean observed peak lactate level+/-SD was 10.3+/-5 mmol/L. After discontinuation of stavudine treatment, lactic acidosis improved in 4 patients after 4-60 weeks, and 1 patient died. Evaluations for other causes of lactic acidosis, including hypoxemia, malignancy, sepsis, and cardiogenic shock, were negative.


A genome-wide search for human type 1 diabetes susceptibility genes.
We have searched the human genome for genes that predispose to type 1 (insulin-dependent) diabetes mellitus using semi-automated fluorescence-based technology and linkage analysis. In addition to IDDM1 (in the major histocompatibility complex on chromosome 6p21) and IDDM2 (in the insulin gene region on chromosome 11p15), eighteen different chromosome regions showed some positive evidence of linkage to disease. Linkages to chromosomes 11q (IDDM4) and 6q (IDDM5) were confirmed by replication, and chromosome 18 may encode a fifth disease locus. There are probably no genes with large effects aside from IDDM1. Therefore polygenic inheritance is indicated, with a major locus at the major histocompatibility complex.


The epidemiology workforce: are we planning for the future?
Epidemiology has a central role in public health practice, education and research, and is arguably the only discipline unique to public health. A strong perception exists among epidemiologists in Australia that there is a substantial shortage in epidemiological capacity within the health workforce and health research, and that there are few graduates with sufficient high-level epidemiological training to fill the educational and leadership roles that will be essential to building this capacity. It was this concern that led the Australasian Epidemiological Association (AEA)--the peak professional body for epidemiologists in Australia and New Zealand--to convene a working group in 2007 to assess and address these concerns. This article summarises the key training challenges and opportunities discussed within this group, and the larger organisation, with the intention of stimulating greater public debate of these issues.


Voxel-based morphometry to discriminate early Alzheimer's disease from controls.
We assessed the accuracy of voxel-based morphometry (VBM) using a three-dimensional T1-weighted MRI in discriminating Alzheimer's disease (AD) in the very early stage of amnestic type of mild cognitive impairment and age-matched healthy controls. We randomly divided these subjects into two groups. The first group comprising 30 AD patients and 41 controls was used to identify the area with the most significant gray matter loss in patients compared to normal controls based on the voxel-based analysis of a group comparison. The second group comprising 31 patients and 41 controls was used to determine the discrimination accuracy of VBM. A Z-score map for a gray matter image of a subject was obtained by comparison with mean and standard deviation gray matter images of the controls for each voxel after anatomical standardization and voxel normalization to global mean using the following equation; Z-score=([control mean]-[individual value])/(control S.D.). Receiver operating characteristic curves for a Z-score in the bilateral medial temporal areas including the entorhinal cortex with the most significant loss in the first group showed a high discrimination accuracy of 87.8%. This result would open up a possibility for early diagnosis of AD using VBM.


The structure and activity of the glutathione reductase from Streptococcus pneumoniae.
The glutathione reductase (GR) from Streptococcus pneumoniae is a flavoenzyme that catalyzes the reduction of oxidized glutathione (GSSG) to its reduced form (GSH) in the cytoplasm of this bacterium. The maintenance of an intracellular pool of GSH is critical for the detoxification of reactive oxygen and nitrogen species and for intracellular metal tolerance to ions such as zinc. Here, S. pneumoniae GR (SpGR) was overexpressed and purified and its crystal structure determined at 2.56 Å resolution. SpGR shows overall structural similarity to other characterized GRs, with a dimeric structure that includes an antiparallel β-sheet at the dimer interface. This observation, in conjunction with comparisons with the interface structures of other GR enzymes, allows the classification of these enzymes into three classes. Analyses of the kinetic properties of SpGR revealed a significantly higher value for Km(GSSG) (231.2 ± 24.7 µM) in comparison to other characterized GR enzymes.


A gene profiling deconvolution approach to estimating immune cell composition from complex tissues.
A new emerged cancer treatment utilizes intrinsic immune surveillance mechanism that is silenced by those malicious cells. Hence, studies of tumor infiltrating lymphocyte populations (TILs) are key to the success of advanced treatments. In addition to laboratory methods such as immunohistochemistry and flow cytometry, in silico gene expression deconvolution methods are available for analyses of relative proportions of immune cell types. Herein, we used microarray data from the public domain to profile gene expression pattern of twenty-two immune cell types. Initially, outliers were detected based on the consistency of gene profiling clustering results and the original cell phenotype notation. Subsequently, we filtered out genes that are expressed in non-hematopoietic normal tissues and cancer cells. For every pair of immune cell types, we ran t-tests for each gene, and defined differentially expressed genes (DEGs) from this comparison. Equal numbers of DEGs were then collected as candidate lists and numbers of conditions and minimal values for building signature matrixes were calculated. Finally, we used v -Support Vector Regression to construct a deconvolution model. The performance of our system was finally evaluated using blood biopsies from 20 adults, in which 9 immune cell types were identified using flow cytometry. The present computations performed better than current state-of-the-art deconvolution methods. Finally, we implemented the proposed method into R and tested extensibility and usability on Windows, MacOS, and Linux operating systems. The method, MySort, is wrapped as the Galaxy platform pluggable tool and usage details are available at https://testtoolshed.g2.bx.psu.edu/view/moneycat/mysort/e3afe097e80a .


Race and Equity in Statewide Implementation Programs: An Application of the Policy Ecology of Implementation Framework.
Although the literature is growing regarding large-scale, system-wide implementation programs, the broader political and social contexts, including race and ethnicity, are frequently ignored. Using the Policy Ecology of Implementation framework (Raghavan et al., Implement Sci 3:26, 2008), Minnesota's CEMIG is examined to investigate the role of social and political contexts in the implementation process and the barriers they create. Data from 22 interview transcripts from DHS administrators, agency grant managers, university educators, advocacy group representatives, and mental health board members, along with more than 1000 grant documents were qualitatively analyzed using content analysis to reveal three themes concerning how the participants experienced program implementation: invisibility, isolation, and inequity. Findings demonstrate the participants perceived that the grant program perpetuated inequities by neglecting to promote the program, advocate for clinicians of color, and coordinate isolated policy ecology systems. Strategies for future large-scale, system-wide mental health program implementation are provided.


[Morbidity profile and the standard of access to health services for elderly practitioners of physical activities].
The morbidity profile and access to health services of 132 women and 33 men, with average age of 69.1 ± 6 years--all practitioners of physical activities was--analyzed. A questionnaire for the socio-demographic profile, physical activity involved, self-referred morbidity and access to health services was applied. In the analysis, descriptive and inferencial statistics were used, with a significance level of 5%. Most of the sample was 60-69 years old (55.7%), practicing water aerobics (52.7%) and had high blood pressure (48.4%). The women aged 60 to 69 years (p <0.05) and 70 to 79 years (p <0.05) had at least one chronic disease. The indicators of access to health services were similar between genders (p> 0.05). The younger-aged men went more often to a doctor during the last year than the younger-aged women (p <0.05). In the other age brackets, feminine hegemony was maintained, with significant difference for 70 to 79 year-old females (p <0.05). Most of the elderly sought their private doctor (33.3%) or a health center (27.8 %). The main problems of the health services were medication (64.8%) and delays in scheduling consultations (48.4%). It was noted that the elderly are worried about preventive healthcare, which can be linked to the benefits of the practice of physical activity.


Frontal and parietal lobe involvement in the processing of pretence and intention.
We assessed whether different processes might be at play during pretence understanding by examining breakdowns of performance in participants with acquired brain damage. In Experiment 1 patients with frontal or parietal lesions and neurologically intact adults were asked to categorize videos of pretend and real actions. In Experiment 2 participants saw three types of videos: real intentional actions, real accidental actions, and pretend actions. In one session they judged whether the actions they saw were intentional or accidental, and in a second session they judged whether the actions were real or pretend. Parietal patients had particular difficulties in the identification of pretend actions, and both parietal and frontal patients were more impaired than controls in understanding the intentional nature of pretence. Analyses of individual patients' performance revealed that parietal lesions, and in particular lesions to the temporo-parietal junction, impaired the ability to discriminate pretend from real actions. However, this did not necessarily affect the discrimination of intentional from unintentional actions, which instead may be independently disrupted by damage to frontal areas. Moreover, spared ability to discriminate pretend actions from real actions, and intentional actions from accidental actions, did not grant a full conceptual understanding of the intentional nature of pretence. The implications for pretence understanding are discussed.