Magnetic resonance imaging assessment of intraventricular dyssynchrony and delayed enhancement as predictors of response to cardiac resynchronization therapy in patients with heart failure of ischaemic and non-ischaemic etiologies.
To assess the value of dyssynchrony and myocardial viability assessment by cardiac magnetic resonance (CMR) in prediction of response to cardiac resynchronization therapy (CRT) in patients with heart failure (HF) of both ischaemic and non-ischaemic etiologies. Patients scheduled for CRT in NYHA class II-IV, left ventricular ejection fraction <35%, QRS ≥ 120 ms were included. Tagged cine and late gadolinium enhancement (LGE) images were performed. Dyssynchrony was assessed with inTag toolbox and LGE was quantified using cutoff value at half of maximal signal in the scar. Cardiopulmonary exercise test, echocardiography and blood testing for NT-proBNP levels were done at baseline and 6 months after CRT. 52 patients (age 60.3 ± 13 years) were included. 26 patients (50%) met response criteria. The ischaemic etiology of HF was more frequent (69% vs. 31%, p=0.002), the percent of LGE was higher (7.7% [0-13.5%] vs. 19.0% (0-31.9%], p=0.013), regional vector of circumferential strain variance (RVV) was lower (0.27 ± 0.08 vs. 0.34 ± 0.09, p=0.009) and uniformity of radial strain was higher (0.72 ± 0.25 vs. 0.56 ± 0.29, p=0.046) in non-responders vs. responders. Multivariate logistic regression showed that RVV predicted response to CRT (HR 2.3, 95% CI 1.02-5.02, p=0.0430) independently of LGE and the etiology of heart failure. In the subgroup of patients with ischaemic HF the extend of transmural scar within myocardium was higher in non-responders vs. responders (26.3% vs. 15.0% respectively, p=0.01) and was a predictor of response to CRT in univariable analysis (HR 0.87, 95% CI 0.77-0.98, p=0.025) providing the sensitivity of 76% and specificity of 75% at the cutoff point of 18% in the prediction of poor response to CRT. In patients with non-ischaemic HF QRS was wider (162 ms vs. 140 ms, p=0.04), regional vector of strain variance (RVV) was higher (0.39 vs. 0.25, p=0.002) and uniformity of radial strain was lower (0.52 vs. 0.80, p=0.049) in non-responders vs. responders. Univariable logistic regression showed that RVV was a predictor of response to CRT (HR 1.50, 95% CI 1.06-2.13, p=0.022), providing the sensitivity of 94% and specificity of 85% at the cutoff point of 0.31. CMR derived parameters of dyssynchrony such as RVV may provide an additive value in prediction of response to CRT, especially in patients with non-ischaemic etiology of heart failure. In patients with ischaemic HF the transmurality of LGE is an important predictor of lack of response to CRT.


Preventing mother-to-child transmission: factors affecting mothers' choice of feeding--a case study from Cameroon.
This paper reports on factors influencing the decision of mothers regarding the type of feeding method for their babies in a rural setting in Cameroon. The aim of the study was to ascertain the proportion of mothers choosing the different methods of feeding, to determine the various factors influencing their choices, and to ascertain the relationships of these factors to their respective choices. Questionnaires were used on 108 HIV-positive mothers who had delivered babies and who were administered nevirapine at least 3 months prior to the study. A focus group discussion with mothers also took place. Findings were that more mothers (84%) chose breastfeeding than artificial feeding (16%), while a minority (4%) selected mixed feeding. Factors found to militate against artificial feeding were cost (69%), stigma (64%), family pressure (44%), inconvenience in preparation/administration (38%), prior education from health workers (23%), and loss of special attention from family (8%). On the other hand, advice of health worker (44%), ill health (19.5%), free milk (12.5%),job pressure (12.5%) and loss of beauty (12.5%) were found to militate against breastfeeding. A direct relationship was also found between age, educational level, income size, marital status and choice of feeding. Policies targeting stigma reduction and socio-cultural factors affecting the choice of feeding are needed to optimise uptake of the less risky methods of feeding which could in turn contribute to a reduction in transmission.


The Perception and Estimation of Others' Pain according to Children.
Accurate interpretation of pain expressed by others is important for socialization; however, the development of this skill in children is still poorly understood. Empathy for pain models propose two main components (affective and cognitive), which develop at different stages of life. The study's objective was to investigate the children's ability between 3 and 12 years of age to detect and assess the pain intensity in others using visual stimuli depicting either facial expressions of pain or hands in painful contexts. 40 preschool children and 62 school-aged children were recruited. Children observed series of stimuli and evaluated the pain intensity depicted. Results demonstrated that children as young as three years old were able to detect and assess pain in both types of stimuli and this ability continued to improve until the age of 12. Participants demonstrated better detection performance with hands than with faces. Results were coherent with the idea that the two types of stimuli presented recruit different processes. Pain detection in hands appears to rely mostly on affective sharing processes that are effective early in life, while older children's higher ability to perceive pain in facial expressions suggests that this ability is associated with the gradual development of cognitive processes.


Anti-influenza virus effect of aqueous extracts from dandelion.
Human influenza is a seasonal disease associated with significant morbidity and mortality. Anti-flu Traditional Chinese Medicine (TCM) has played a significant role in fighting the virus pandemic. In TCM, dandelion is a commonly used ingredient in many therapeutic remedies, either alone or in conjunction with other natural substances. Evidence suggests that dandelion is associated with a variety of pharmacological activities. In this study, we evaluated anti-influenza virus activity of an aqueous extract from dandelion, which was tested for in vitro antiviral activity against influenza virus type A, human A/PR/8/34 and WSN (H1N1). Results obstained using antiviral assays, minigenome assay and real-time reverse transcription-PCR analysis showed that 0.625-5 mg/ml of dandelion extracts inhibited infections in Madin-Darby canine kidney (MDCK) cells or Human lung adenocarcinoma cell line (A549) of PR8 or WSN viruses, as well as inhibited polymerase activity and reduced virus nucleoprotein (NP) RNA level. The plant extract did not exhibit any apparent negative effects on cell viability, metabolism or proliferation at the effective dose. This result is consistent with the added advantage of lacking any reported complications of the plant's utility in traditional medicine over several centuries. The antiviral activity of dandelion extracts indicates that a component or components of these extracts possess anti-influenza virus properties. Mechanisms of reduction of viral growth in MDCK or A549 cells by dandelion involve inhibition on virus replication.


Dual ancestries and ecologies of the Late Glacial Palaeolithic in Britain.
Genetic investigations of Upper Palaeolithic Europe have revealed a complex and transformative history of human population movements and ancestries, with evidence of several instances of genetic change across the European continent in the period following the Last Glacial Maximum (LGM). Concurrent with these genetic shifts, the post-LGM period is characterized by a series of significant climatic changes, population expansions and cultural diversification. Britain lies at the extreme northwest corner of post-LGM expansion and its earliest Late Glacial human occupation remains unclear. Here we present genetic data from Palaeolithic human individuals in the United Kingdom and the oldest human DNA thus far obtained from Britain or Ireland. We determine that a Late Upper Palaeolithic individual from Gough's Cave probably traced all its ancestry to Magdalenian-associated individuals closely related to those from sites such as El Mirón Cave, Spain, and Troisième Caverne in Goyet, Belgium. However, an individual from Kendrick's Cave shows no evidence of having ancestry related to the Gough's Cave individual. Instead, the Kendrick's Cave individual traces its ancestry to groups who expanded across Europe during the Late Glacial and are represented at sites such as Villabruna, Italy. Furthermore, the individuals differ not only in their genetic ancestry profiles but also in their mortuary practices and their diets and ecologies, as evidenced through stable isotope analyses. This finding mirrors patterns of dual genetic ancestry and admixture previously detected in Iberia but may suggest a more drastic genetic turnover in northwestern Europe than in the southwest.


Burden of illness in cancer survivors: findings from a population-based national sample.
Population trends in aging and improved cancer survival are likely to result in increased cancer prevalence in the United States, but few estimates of the burden of illness among cancer survivors are currently available. The purpose of this study was to estimate the burden of illness in cancer survivors in a national, population-based sample. A total of 1823 cancer survivors and 5469 age-, sex-, and educational attainment-matched control subjects were identified from the 2000 National Health Interview Survey. Multiple measures of burden, including utility, a summary measure of health, and days lost from work, were compared using two-sided tests of statistical significance for the two groups overall and for subgroups stratified by tumor site and time since diagnosis. Compared with matched control subjects, cancer survivors had poorer outcomes across all burden measures (P<.01). Cancer survivors had lower utility values (0.74 versus 0.80; P<.001) and higher levels of lost productivity and were more likely to report their health as fair or poor (31.0% versus 17.9%; P<.001) than matched control subjects. Cancer survivors reported statistically significantly higher burden than did control subjects across tumor sites and across time since diagnosis (i.e., within the past year, 2-5 years, 6-10 years, and > or =11 years for the majority of measures. Cancer survivors have poorer health outcomes than do similar individuals without cancer across multiple burden measures. These decrements are consistent across tumor sites and are found in patients many years following reported diagnosis. Improved measurement of long-term burden of illness will be important for future prospective research.


Effect of ion structure on nanoscale friction in protic ionic liquids.
The effect of ionic liquid (IL) molecular structure on nanoscale friction has been investigated using colloidal probe Friction Force Microscopy (FFM). The ILs studied were ethylammonium formate (EAF), ethylammonium nitrate (EAN), propylammonium formate (PAF), propylammonium nitrate (PAN), dimethylethylammonium formate (DMEAF), and ethanolammonium nitrate (EtAN). ILs were confined between a silica colloid probe and a mica surface, and the friction force was measured as a function of normal load for sliding velocities between 10 and 40 μm s(-1). At low normal forces, multiple IL layers are found between the probe and the surface, but at higher force, in the boundary layer regime, a single ion layer separates the probe and the surface. In the boundary layer regime energy is dissipated by two main pathways. Firstly, the ionic liquid near the surface, with the exception of the boundary layer, is expelled from the advancing contact made by the probe on the surface. This disruption in the interactions between the boundary layer and the near surface multilayers, leads to energy dissipation and depends on the strength of the attraction between the boundary and near surface layers. The second pathway is via rotations and twists of ions in the boundary layer, primarily associated with the cation terminal methyl group. The friction coefficient did not vary over the limited range of sliding speeds investigated.


Expression of type I interferon-associated genes at antiretroviral therapy interruption predicts HIV virological rebound.
Although certain individuals with HIV infection can stop antiretroviral therapy (ART) without viral load rebound, the mechanisms under-pinning 'post-treatment control' remain unclear. Using RNA-Seq we explored CD4 T cell gene expression to identify evidence of a mechanism that might underpin virological rebound and lead to discovery of associated biomarkers. Fourteen female participants who received 12 months of ART starting from primary HIV infection were sampled at the time of stopping therapy. Two analysis methods (Differential Gene Expression with Gene Set Enrichment Analysis, and Weighted Gene Co-expression Network Analysis) were employed to interrogate CD4+ T cell gene expression data and study pathways enriched in post-treatment controllers versus early rebounders. Using independent analysis tools, expression of genes associated with type I interferon responses were associated with a delayed time to viral rebound following treatment interruption (TI). Expression of four genes identified by Cox-Lasso (ISG15, XAF1, TRIM25 and USP18) was converted to a Risk Score, which associated with rebound (p < 0.01). These data link transcriptomic signatures associated with innate immunity with control following stopping ART. The results from this small sample need to be confirmed in larger trials, but could help define strategies for new therapies and identify new biomarkers for remission.


Modeling, Simulation, and Implementation of Solar-Driven Water-Splitting Devices.
An integrated cell for the solar-driven splitting of water consists of multiple functional components and couples various photoelectrochemical (PEC) processes at different length and time scales. The overall solar-to-hydrogen (STH) conversion efficiency of such a system depends on the performance and materials properties of the individual components as well as on the component integration, overall device architecture, and system operating conditions. This Review focuses on the modeling- and simulation-guided development and implementation of solar-driven water-splitting prototypes from a holistic viewpoint that explores the various interplays between the components. The underlying physics and interactions at the cell level is are reviewed and discussed, followed by an overview of the use of the cell model to provide target properties of materials and guide the design of a range of traditional and unique device architectures.


Calcium channel blocker monotherapy versus combination with renin-angiotensin system inhibitors on the development of new-onset diabetes mellitus in hypertensive Korean patients.
In real practice, two or more antihypertensive drugs are needed to achieve target blood pressure. We investigated the comparative beneficial actions of combination therapy of renin-angiotensin system inhibitors (RASI), with calcium channel blockers (CCB) over CCB monotherapy on the development of new-onset diabetes mellitus (NODM) in Korean patients during four-year follow-up periods. A total of 3208 consecutive hypertensive patients without a history of diabetes mellitus who had been prescribed CCB were retrospectively enrolled from January 2004 to December 2012. These patients were divided into the two groups according to the additional use of RASI (the RASI group, n = 1221 and the no RASI group, n = 1987). Primary endpoint was NODM, defined as a fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%. Secondary endpoint was major adverse cardiac events (MACE) defined as total death, myocardial infarction (MI) and percutaneous coronary intervention (PCI). After propensity score-matched (PSM) analysis, two propensity-matched groups (939 pairs, n = 1878, C-statistic = 0.743) were generated. The incidences of NODM (HR = 1.009, 95% CI: 0.700-1.452, P = 0.962), MACE (HR = 0.877, 95% CI: 0.544-1.413, P = 0.589), total death, MI, PCI were similar between the two groups after PSM during four years. The use of RASI in addition to CCB showed comparable incidences of NODM and MACE compared to CCB monotherapy in non-diabetic hypertensive Korean patients during four-year follow-up period. However, large-scaled randomized controlled clinical trials will be required for a more definitive conclusion.


Emerging challenges in regulatory T cell function and biology.
Much progress has been made in understanding how the immune system is regulated, with a great deal of recent interest in naturally occurring CD4+ regulatory T cells that actively engage in the maintenance of immunological self-tolerance and immune homeostasis. The challenge ahead for immunologists is the further elucidation of the molecular and cellular processes that govern the development and function of these cells. From this, exciting possibilities are emerging for the manipulation of regulatory T cell pathways in treating immunological diseases and suppressing or augmenting physiological immune responses.


Epigenetic regulation of the Wnt signaling inhibitor DACT2 in human hepatocellular carcinoma.
DACT2 (Dapper, Dishevelled-associated antagonist of β-catenin homolog 2) is a member of the DACT family involved in the regulation of embryonic development. Human DACT2 is localized on 6q27, a region of frequent loss of heterozygosity in human cancers. However, the regulation of DACT2 expression and function in hepatocellular carcinoma (HCC) remains unclear. In this study, genetic and epigenetic changes of DACT2 were analyzed in HCC cell lines and primary cancer. We found no single-nucleotide polymorphism (SNP) associated with HCC. Promoter region methylation was correlated with loss or reduction of DACT2 expression, and restoration of DACT2 expression was induced by 5-aza-2'-deoxycytidine (5-AZA) in HCC cell lines. Promoter region methylation was found in 54.84% of primary HCC. Reduction of DACT2 expression was associated with promoter hypermethylation, and expression of DACT2 was inversely related to β-catenin expression in primary HCC. DACT2 suppressed cell proliferation, induced G 2-M arrest in cell lines and inhibited tumor growth in xenograft nude mice. The transcriptional activity of TCF-4 and the expression of Wnt signaling downstream genes were suppressed by DACT2 re-expression and reactivated by depletion of DACT2. In conclusion, DACT2 is frequently methylated in HCC and its expression is regulated by promoter hypermethylation. DACT2 suppresses HCC by inhibiting Wnt signaling in human HCC.


Are associations between electronic media use and BMI different across levels of physical activity?
The use of electronic media has been found to be a risk factor for higher BMI and for being overweight. Physical activity has been found to be associated with lower BMI and lower risk for being overweight. Little is known about whether the associations between physical activity and electronic media use are additive or interactive in predicting BMI and risk for overweight among adolescents. The data used in this study stem from the 2009/2010 survey of "Health Behaviour in School-aged Children (HBSC) study: A WHO Cross-National Survey. The sample consisted of 107184 13 and 15 year students from 30 different countries. Multilevel regression models were used to produce the presented estimates. Overall, 18% of boys and 11% of girls were classified as overweight. EM use was found to be associated with increased BMI z-scores and odds for overweight among both boys and girls who did not comply with physical activity guidelines. Among physically active adolescents, EM was found to be significantly associated with BMI or odds for overweight among girls, but not among boys. While the usage of EM appear to be inconsequential for BMI and the risk of overweight among physically active boys, we find evidence indicating that EM use is associated with BMI and risk for overweight among girls, including those who report complying with MVPA guidelines.


Excitation of self-transparency Bragg solitons in quadratic media.
We show that self-transparent or gap solitons with leading-order components at fundamental frequency can be generated in a singly resonant Bragg grating by second-harmonic generation. We discuss the conditions required for exciting these localized waves.


Patient adherence to tuberculosis treatment: a systematic review of qualitative research.
Tuberculosis (TB) is a major contributor to the global burden of disease and has received considerable attention in recent years, particularly in low- and middle-income countries where it is closely associated with HIV/AIDS. Poor adherence to treatment is common despite various interventions aimed at improving treatment completion. Lack of a comprehensive and holistic understanding of barriers to and facilitators of, treatment adherence is currently a major obstacle to finding effective solutions. The aim of this systematic review of qualitative studies was to understand the factors considered important by patients, caregivers and health care providers in contributing to TB medication adherence. We searched 19 electronic databases (1966-February 2005) for qualitative studies on patients', caregivers', or health care providers' perceptions of adherence to preventive or curative TB treatment with the free text terms "Tuberculosis AND (adherence OR compliance OR concordance)". We supplemented our search with citation searches and by consulting experts. For included studies, study quality was assessed using a predetermined checklist and data were extracted independently onto a standard form. We then followed Noblit and Hare's method of meta-ethnography to synthesize the findings, using both reciprocal translation and line-of-argument synthesis. We screened 7,814 citations and selected 44 articles that met the prespecified inclusion criteria. The synthesis offers an overview of qualitative evidence derived from these multiple international studies. We identified eight major themes across the studies: organisation of treatment and care; interpretations of illness and wellness; the financial burden of treatment; knowledge, attitudes, and beliefs about treatment; law and immigration; personal characteristics and adherence behaviour; side effects; and family, community, and household support. Our interpretation of the themes across all studies produced a line-of-argument synthesis describing how four major factors interact to affect adherence to TB treatment: structural factors, including poverty and gender discrimination; the social context; health service factors; and personal factors. The findings of this study are limited by the quality and foci of the included studies. Adherence to the long course of TB treatment is a complex, dynamic phenomenon with a wide range of factors impacting on treatment-taking behaviour. Patients' adherence to their medication regimens was influenced by the interaction of a number of these factors. The findings of our review could help inform the development of patient-centred interventions and of interventions to address structural barriers to treatment adherence.


The Limited Utility of Ranking Hospitals Based on Their Colon Surgery Infection Rates.
The Centers for Medicare and Medicaid Services (CMS) use colon surgical site infection (SSI) rates to rank hospitals and apply financial penalties. The CMS' risk-adjustment model omits potentially impactful variables that might disadvantage hospitals with complex surgical populations. We analyzed adult patients who underwent colon surgery within facilities associated with HCA Healthcare from 2014 to 2016. SSIs were identified from National Health Safety Network (NHSN) reporting. We trained and validated 3 SSI prediction models, using (1) current CMS model variables, including hospital-specific random effects (HCA-adapted CMS model); (2) demographics and claims-based comorbidities (expanded-claims model); and (3) demographics, claims-based comorbidities, and NHSN variables (claims-plus-electronic health record [EHR] model). Discrimination, calibration, and resulting rankings were compared among all models and the current CMS model with published coefficient values. We identified 39 468 colon surgeries in 149 hospitals, resulting in 1216 (3.1%) SSIs. Compared to the HCA-adapted CMS model, the expanded-claims model had similar performance (c-statistic, 0.65 vs 0.67, respectively), while the claims-plus-EHR model was more accurate (c-statistic, 0.70; 95% confidence interval, .67-.73; P = .004). The sampling variation, due to the low surgical volume and small number of infections, contributed 74% of the total variation in observed SSI rates between hospitals. When CMS model rankings were compared to those from the expanded-claims and claims-plus-EHR models, 18 (15%) and 26 (22%) hospitals changed quartiles, respectively, and 10 (8.3%) and 12 (10%) hospitals changed into or out of the lowest-performing quartile, respectively. An expanded set of variables improved colon SSI risk predictions and quartile assignments, but low procedure volumes and SSI events remain a barrier to effectively comparing hospitals.


Bi2SiO5@g-SiO2 upconverting nanoparticles: a bismuth-driven core-shell self-assembly mechanism.
Core-shell systems have attracted increasing interest among the research community in recent years due to their unique properties and structural features, and the development of new synthetic strategies is still a challenge. In this work, we have investigated lanthanide-doped Bi2SiO5 nanocrystal formation inside mesoporous silica nanoparticles (MSNs). The role of both synthesis temperature and concentration of the bismuth precursor impregnated into the MSNs is discussed, showing an unprecedented strategy for the simultaneous stabilization of a crystalline core and a glassy shell. Temperature dependent synchrotron radiation X-ray powder diffraction (SR-XRPD) and high resolution transmission electron microscopy (HR-TEM) analyses allow one to follow the crystalline core growth. A mechanism for the formation of a Bi2SiO5@g-SiO2 core-shell nanosystem is proposed. In addition, the easy tunability of the color output of the upconverting system is demonstrated by means of suitable doping lanthanide ions with potential applications in several fields.


Ala-9Val polymorphism of Mn-SOD gene in sickle cell anemia.
Oxidative stress may be contributory to the pathophysiology of the abnormalities that underlie the clinical course of sickle cell anemia. We looked for a possible genetic association between the functional polymorphism Ala-9Val in the human Mn-SOD gene and sickle cell anemia. One hundred and twenty-seven patients with sickle cell anemia and 127 healthy controls were recruited into the study. Alanine versus valine polymorphism in the signal peptide of the Mn-SOD gene was evaluated using a primer pair to amplify a 107-bp fragment followed by digestion with the restriction enzyme NgoMIV. In the sickle cell anemia patients, the frequency of Val/Val genotype was approximately 1.4-fold lower and that of Ala/Val was 1.3-fold higher compared to the controls. No significant difference in genotype frequencies was found between patients and controls (χ(2) = 4.561, d.f. = 2, P = 0.101). The Val-9 was the most common allele in patient and healthy subjects. No significant difference in allele frequencies was found between patients and controls (χ(2) = 1.496, d.f. = 1, P = 0.221). We conclude that the Mn-SOD gene polymorphism is not associated with sickle cell anemia.


Severe male factor in in vitro fertilization: definition, prevalence, and treatment. An update.
Infertility affects 10%-15% of couples worldwide. Of all infertility cases, 20%-70% are due to male factors. In the past, men with severe male factor (SMF) were considered sterile. Nevertheless, the development of intracytoplasmic sperm injection (ICSI) drastically modified this scenario. The advances in assisted reproductive technology (ART), specifically regarding surgical sperm retrieval procedures, allowed the efficacious treatment of these conditions. Yet, before undergoing ICSI, male factor infertility requires careful evaluation of clinical and lifestyle behavior together with medical treatment. Epidemiologically speaking, women whose male partner is azoospermic tend to be younger and with a better ovarian reserve. These couples, in fact, are proposed ART earlier in their life, and for this reason, their ovarian response after stimulation is generally good. Furthermore, in younger couples, azoospermia can be partially compensated by the efficient ovarian response, resulting in an acceptable fertility rate following in vitro fertilization (IVF) techniques. Conversely, when azoospermia is associated with a reduced ovarian reserve and/or advanced maternal age, the treatment becomes more challenging, with a consequent reduction in IVF outcomes. Nonetheless, azoospermia seems to impair neither the euploidy rate at the blastocyst stage nor the implantation of euploid blastocysts. Based on the current knowledge, the assessment of male infertility factors should involve: (1) evaluation - to diagnose and quantify seminologic alterations; (2) potentiality - to determine the real possibilities to improve sperm parameters and/or retrieve spermatozoa; (3) time - to consider the available "treatment window", based on maternal age and ovarian reserve. This review represents an update of the definition, prevalence, causes, and treatment of SMF in a modern ART clinic.


The role of eosinophils in non-parasitic infections.
Eosinophils are a subset of leukocytes traditionally associated with Th2-related diseases and helminth infections. However, accumulating evidence suggests eosinophils play a more prominent role in the immune response to bacterial and viral pathogens than previously realized. Specifically, eosinophils possess antimicrobial properties against a broad range of pathogens, and release specific and secondary granules as a result of pathogen recognition. Pathogen recognition is accomplished through expression of Toll-like receptors, as well as other surface and intracellular receptors expressed by the eosinophil. Interestingly, specific killing mechanisms employed by each granule protein differ based on pathogen recognition, but ultimately release of eosinophil granules leads to direct killing of many different pathogens. The precise mechanisms of killing by granule proteins and the circumstances in which specific proteins are secreted are only now being determined. Future efforts to understand these mechanisms may lead toward clinical use of granule proteins as antimicrobial agents in humans, in addition to revealing implications regarding the use of eosinophil-depleting therapies for allergic disorders. This review will summarize the literature to date regarding the role of eosinophils in non-parasitic infections.


Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer.
Concurrent chemoradiotherapy is the standard-of-care curative treatment for many cancers but is associated with substantial morbidity. Concurrent chemoradiotherapy administered with proton therapy might reduce toxicity and achieve comparable cancer control outcomes compared with conventional photon radiotherapy by reducing the radiation dose to normal tissues. To assess whether proton therapy in the setting of concurrent chemoradiotherapy is associated with fewer 90-day unplanned hospitalizations (Common Terminology Criteria for Adverse Events, version 4 [CTCAEv4], grade ≥3) or other adverse events and similar disease-free and overall survival compared with concurrent photon therapy and chemoradiotherapy. This retrospective, nonrandomized comparative effectiveness study included 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent from January 1, 2011, through December 31, 2016, at a large academic health system. Three hundred ninety-one patients received proton therapy and 1092, photon therapy. Data were analyzed from October 15, 2018, through February 1, 2019. Proton vs photon chemoradiotherapy. The primary end point was 90-day adverse events associated with unplanned hospitalizations (CTCAEv4 grade ≥3). Secondary end points included Eastern Cooperative Oncology Group (ECOG) performance status decline during treatment, 90-day adverse events of at least CTCAEv4 grade 2 that limit instrumental activities of daily living, and disease-free and overall survival. Data on adverse events and survival were gathered prospectively. Modified Poisson regression models with inverse propensity score weighting were used to model adverse event outcomes, and Cox proportional hazards regression models with weighting were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach. Among the 1483 patients included in the analysis (935 men [63.0%]; median age, 62 [range, 18-93] years), those receiving proton therapy were significantly older (median age, 66 [range, 18-93] vs 61 [range, 19-91] years; P < .01), had less favorable Charlson-Deyo comorbidity scores (median, 3.0 vs 2.0; P < .01), and had lower integral radiation dose to tissues outside the target (mean [SD] volume, 14.1 [6.4] vs 19.1 [10.6] cGy/cc × 107; P < .01). Baseline grade ≥2 toxicity (22% vs 24%; P = .37) and ECOG performance status (mean [SD], 0.62 [0.74] vs 0.68 [0.80]; P = .16) were similar between the 2 cohorts. In propensity score weighted-analyses, proton chemoradiotherapy was associated with a significantly lower relative risk of 90-day adverse events of at least grade 3 (0.31; 95% CI, 0.15-0.66; P = .002), 90-day adverse events of at least grade 2 (0.78; 95% CI, 0.65-0.93; P = .006), and decline in performance status during treatment (0.51; 95% CI, 0.37-0.71; P < .001). There was no difference in disease-free or overall survival. In this analysis, proton chemoradiotherapy was associated with significantly reduced acute adverse events that caused unplanned hospitalizations, with similar disease-free and overall survival. Prospective trials are warranted to validate these results.


Functional connectivity and cannabis use in high-risk adolescents.
Adolescence is a unique neurodevelopmental period when regions of the brain most able to assess risk and reward are still in development. Cannabis use during adolescence has been associated with persistent negative outcomes. Although measures of resting brain activity are useful in assessing functional connectivity, such measures have not been broadly applied in adolescent cannabis-users. The goal of the present study was to analyze the associations between cannabis use and resting brain activity in a sample of high-risk adolescents. Eighty-two high-risk youth between 14-18 years old were recruited from a juvenile justice day program. Youth completed a brief neurocognitive battery including assessments of cannabis use and a 5-minute resting functional magnetic resonance imaging (fMRI) scan. Intrinsic connectivity networks were extracted using the GIFT toolbox. Brain activity in a fronto-temporal network was compared in youth with high cannabis use vs. low cannabis use using an independent-samples t-test with alcohol use entered as a covariate. Analysis revealed two elements within the fronto-temporal network related to cannabis use: one in middle frontal gyrus related to high cannabis use, and one in middle temporal gyrus related to low cannabis use. Only the frontal source survived application of a cluster size threshold and was significant at p < 0.005. These results are consistent with patterns of activity in adult cannabis-users. The observed effect may reflect either pre-existing risk factors or near-term consequences of cannabis use. Prevention and intervention strategies that address fronto-temporal functioning may be particularly helpful in this population.


Genetic dissection of TrkB activated signalling pathways required for specific aspects of the taste system.
Neurotrophin-4 (NT-4) and brain derived neurotrophic factor (BDNF) bind to the same receptor, Ntrk2/TrkB, but play distinct roles in the development of the rodent gustatory system. However, the mechanisms underlying these processes are lacking. Here, we demonstrate, in vivo, that single or combined point mutations in major adaptor protein docking sites on TrkB receptor affect specific aspects of the mouse gustatory development, known to be dependent on BDNF or NT-4. In particular, mice with a mutation in the TrkB-SHC docking site had reduced gustatory neuron survival at both early and later stages of development, when survival is dependent on NT-4 and BDNF, respectively. In addition, lingual innervation and taste bud morphology, both BDNF-dependent functions, were altered in these mutants. In contrast, mutation of the TrkB-PLCγ docking site alone did not affect gustatory neuron survival. Moreover, innervation to the tongue was delayed in these mutants and taste receptor expression was altered. We have genetically dissected pathways activated downstream of the TrkB receptor that are required for specific aspects of the taste system controlled by the two neurotrophins NT-4 and BDNF. In addition, our results indicate that TrkB also regulate the expression of specific taste receptors by distinct signalling pathways. These results advance our knowledge of the biology of the taste system, one of the fundamental sensory systems crucial for an organism to relate to the environment.


Assessment of the human epidermis model SkinEthic RHE for in vitro skin corrosion testing of chemicals according to new OECD TG 431.
Based on two successfully completed ECVAM validation studies for in vitro skin corrosion testing of chemicals, the National Co-ordinators of OECD Test Guideline Programme endorsed in 2002 two new test guidelines: TG 430 'Transcutaneous Electrical Resistance assay' and TG 431 'Human Skin Model Test'. To allow all suitable in vitro human reconstructed (dermal or epidermal) models to be used for skin corrosion testing, the OECD TG 431 defines general and functional conditions that the model must meet before it will be routinely used for skin corrosion testing. In addition, the guideline requires correct prediction of 12 reference chemicals and assessment of intra- and inter-laboratory variability. To show that the OECD TG 431 concept works, in 2003 ZEBET tested several chemicals from the ECVAM validation trials on the SkinEthic reconstituted human epidermal (RHE) model. Based on knowledge that reconstructed human skin models perform similarly in toxicological studies, it was decided to adopt the validated EpiDerm skin corrosion test protocol and prediction model to the SkinEthic model. After minor technical changes, classifications were obtained in concordance with those reported for the validated human skin models EPISKIN and EpiDerm. To allow adequate determination of inter-laboratory reproducibility, a blind trial was conducted in three laboratories -- ZEBET (D), Safepharm (UK) and BASF (D), in which the 12 endorsed reference chemicals were tested. Results obtained with the SkinEthic epidermal model were reproducible, both within and between laboratories, and over time. Concordance between the in vitro predictions of skin corrosivity potential obtained with the SkinEthic model and the predictions obtained with the accepted tests of OECD TG 430 and TG 431 was very good. The new test was able to distinguish between corrosive and non-corrosive reference chemicals with an accuracy of 93%.


Cryptococcus neoformans capsule biosynthesis and regulation.
The capsule is certainly the most prominent virulence factor in Cryptococcus neoformans: acapsular strains are avirulent, and capsular polysaccharides have a deleterious effect on the immune system. Until very recently, very few genes involved in capsule biosynthesis had been identified - and this despite the existence of a detailed body of work concerning the capsule's composition, structure and their regulation by environmental factors. The tremendous development of experimental tools and techniques suited to the study of C. neoformans biology together with the sequencing of three complete genomes have, over the last three years, enabled the identification of a number of proteins which participate directly in biosynthesis of the capsule or which regulate its size. Even though this knowledge is still preliminary, it gives us a clearer picture of the various events needed for biosynthesis of this fascinating structure.


Blunted cortisol response to acute pre-learning stress prevents misinformation effect in a forced confabulation paradigm.
Research examining the effects of stress on false memory formation has been equivocal, partly because of the complex nature of stress-memory interactions. A major factor influencing stress effects on learning is the timing of stress relative to encoding. Previous work has shown that brief stressors administered immediately before learning enhance long-term memory. Thus, we predicted that brief stress immediately before learning would decrease participants' susceptibility to subsequent misinformation and reduce false memory formation. Eighty-four male and female participants submerged their hand in ice cold (stress) or warm (no stress) water for 3min. Immediately afterwards, they viewed an 8-min excerpt from the Disney movie Looking for Miracles. The next day, participants were interviewed and asked several questions about the video, some of which forced them to confabulate responses. Three days and three weeks later, respectively, participants completed a recognition test in the lab and a free recall test via email. Our results revealed a robust misinformation effect, overall, as participants falsely recognized a significant amount of information that they had confabulated during the interview as having occurred in the original video. Stress, overall, did not significantly influence this misinformation effect. However, the misinformation effect was completely absent in stressed participants who exhibited a blunted cortisol response to the stress, for both recognition and recall tests. The complete absence of a misinformation effect in non-responders may lend insight into the interactive roles of autonomic arousal and corticosteroid levels in false memory development.


Interaction patterns of nurturant support exchanged in online health social networking.
Expressing emotion in online support communities is an important aspect of enabling e-patients to connect with each other and expand their social resources. Indirectly it increases the amount of support for coping with health issues. Exploring the supportive interaction patterns in online health social networking would help us better understand how technology features impacts user behavior in this context. To build on previous research that identified different types of social support in online support communities by delving into patterns of supportive behavior across multiple computer-mediated communication formats. Each format combines different architectural elements, affecting the resulting social spaces. Our research question compared communication across different formats of text-based computer-mediated communication provided on the MedHelp.org health social networking environment. We identified messages with nurturant support (emotional, esteem, and network) across three different computer-mediated communication formats (forums, journals, and notes) of an online support community for alcoholism using content analysis. Our sample consisted of 493 forum messages, 423 journal messages, and 1180 notes. Nurturant support types occurred frequently among messages offering support (forum comments: 276/412 messages, 67.0%; journal posts: 65/88 messages, 74%; journal comments: 275/335 messages, 82.1%; and notes: 1002/1180 messages, 84.92%), but less often among messages requesting support. Of all the nurturing supports, emotional (ie, encouragement) appeared most frequently, with network and esteem support appearing in patterns of varying combinations. Members of the Alcoholism Community appeared to adapt some traditional face-to-face forms of support to their needs in becoming sober, such as provision of encouragement, understanding, and empathy to one another. The computer-mediated communication format may have the greatest influence on the supportive interactions because of characteristics such as audience reach and access. Other factors include perception of community versus personal space or purpose of communication. These results lead to a need for further research.


Optical readout method based on a narrow-strip filter for microcantilever array sensing.
An effective optical readout approach based on a narrow-strip filter is presented to detect bends of a bimaterial microcantilever focal plane array, by which light intensity of the image plane (CCD image sensor plane) can be increased and its uniformity on the image plane effectively enhanced. It reduces the noise equivalent temperature difference of the microcantilever focal plane array IR imaging system and improves uniformity of the IR images. A comparative experiment is designed to verify effectiveness. The experimental results show that the proposed method has advantages of preferable effect.


The fates of the blastomeres of the 16-cell zebrafish embryo.
We present a fate map for the 16-cell-stage blastomeres of the zebrafish embryo Brachydanio rerio. We injected high molecular weight fluorescent dextran into cleavage-stage cells to observe the contributions of the descendants of the first 16 cells to the adult. The patterns derived from these early cells are similar, but not identical among different embryos. Furthermore, two-color injections showed that sister blastomeres at the 16-cell stage regularly contribute to different sets of adult structures. A few of the scored tissues could not be mapped in a manner consistent with the predicted axes. Other tissues were mapped to several of the 16 blastomeres. Many of the tissues map with high probability to a few 16-cell-stage blastomeres. Thus, based on 112 injections in 56 different embryos, we have constructed a fate map by assigning probabilities for the contribution of each blastomere to each of 31 tissues in the 26-hour embryo.


Pupil dilation and constriction in the skate Leucoraja erinacea in a simulated natural light field.
The skate Leucoraja erinacea has an elaborately shaped pupil, whose characteristics and functions have received little attention. The goal of our study was to investigate the pupil response in relation to natural ambient light intensities. First, we took a recently developed sensory-ecological approach, which gave us a tool for creating a controlled light environment for behavioural work: during a field survey, we collected a series of calibrated natural habitat images from the perspective of the skates' eyes. From these images, we derived a vertical illumination profile using custom-written software for quantification of the environmental light field (ELF). After collecting and analysing these natural light field data, we created an illumination set-up in the laboratory, which closely simulated the natural vertical light gradient that skates experience in the wild and tested the light responsiveness - in particular the extent of dilation - of the skate pupil to controlled changes in this simulated light field. Additionally, we measured pupillary dilation and constriction speeds. Our results confirm that the skate pupil changes from nearly circular under low light to a series of small triangular apertures under bright light. A linear regression analysis showed a trend towards smaller skates having a smaller dynamic range of pupil area (dilation versus constriction ratio around 4-fold), and larger skates showing larger ranges (around 10- to 20-fold). Dilation took longer than constriction (between 30 and 45 min for dilation; less than 20 min for constriction), and there was considerable individual variation in dilation/constriction time. We discuss our findings in terms of the visual ecology of L. erinacea and consider the importance of accurately simulating natural light fields in the laboratory.


Maternal and fetal outcome in patients with eclampsia at Murtala Muhammad specialist Hospital Kano, Nigeria.
Eclampsia is a major contributor to maternal and perinatal mortality worldwide. It is much more common in developing countries like Nigeria where presentation is usually late and resources are scarce. The staggering figures of maternal death (46%) reported by the Society of Obstetricians and Gynaecologists of Nigeria (SOGON) in 2004 moved the Kano State government to initiate programs that will reduce maternal mortality in the state. The objectives of this report were; 1) to determine the prevalence of eclampsia at Murtala Muhammad Specialist hospital (MMSH) Kano between April 2008 and May 2009; 2) to determine maternal and fetal outcome in eclamptic patients admitted to MMSH Kano between April 2008 and May 2009. Case records of all patients admitted to MMSH between April 2008 and May 2009 were retrieved and analyzed using Epi-info version 3.2.2 April 2004 (CDC Atlanta, USA). Information extracted includes demographic data, maternal and fetal outcome. A P value of less than 0.05 was considered significant. There were 688 eclamptic patients admitted and 13 943 women delivered during the study period giving a prevalence of 5% of total deliveries. One hundred and twenty six women died giving a maternal mortality ratio (MMR) of 904/100 000, among them 36 were eclamptics. The perinatal mortality rate for the eclamptics was 132/1 000. 81.4% of the women were primigravidas and majority (82.2%) were at term. Almost 83.3% presented within 12 hours of the onset of the fits and nearly half (44.9%) had their convulsion before the onset of labor. The incidence of eclampsia is 5% of total deliveries. Delay in presentation is associated with poor outcome.


Spatial variation in hyperthermia emergency department visits among those with employer-based insurance in the United States - a case-crossover analysis.
Predictions of intense heat waves across the United States will lead to localized health impacts, most of which are preventable. There is a need to better understand the spatial variation in the morbidity impacts associated with extreme heat across the country to prevent such adverse health outcomes. Hyperthermia-related emergency department (ED) visits were obtained from the Truven Health MarketScan(®) Research dataset for 2000-2010. Three measures of daily ambient heat were constructed using meteorological observations from the National Climatic Data Center (maximum temperature, heat index) and the Spatial Synoptic Classification. Using a time-stratified case crossover approach, odds ratio of hyperthermia-related ED visit were estimated for the three different heat measures. Random effects meta-analysis was used to combine the odds ratios for 94 Metropolitan Statistical Areas (MSA) to examine the spatial variation by eight latitude categories and nine U.S. climate regions. Examination of lags for all three temperature measures showed that the odds ratio of ED visit was statistically significant and highest on the day of the ED visit. For heat waves lasting two or more days, additional statistically significant association was observed when heat index and synoptic classification was used as the temperature measure. These results were insensitive to the inclusion of air pollution measures. On average, the maximum temperature on the day of an ED visit was 93.4°F in 'South' and 81.9°F in the 'Northwest' climatic regions of United States. The meta-analysis showed higher odds ratios of hyperthermia ED visit in the central and the northern parts of the country compared to the south and southwest. The results showed spatial variation in average temperature on days of ED visit and odds ratio for hyperthermia ED visits associated with extreme heat across United States. This suggests that heat response plans need to be customized for different regions and the potential role of hyperthermia ED visits in syndromic surveillance for extreme heat.


Tumor mapping of regional immunostaining for p21, p53, and mdm2 in locally advanced bladder carcinoma.
The aim of this study was to elucidate the associations among immunostaining for p53, p21, and mdm2; their respective expression within each tumor; and the value of these variables for predicting treatment outcome after cystectomy for patients with locally advanced bladder carcinoma. The hospital records from all 173 patients treated with cystectomy for locally advanced urothelial bladder carcinoma between 1967 and 1992 were retrospectively reviewed. Three consecutive sections from biopsies taken before any treatment were stained using the standard immunohistochemical technique for p53, p21, and mdm2, respectively. The cutoff limit was 20% or more for positive p53 expression and 10% or more for positive p21 and mdm2 expression. Positive immunostaining was observed for p53 in 98 tumors (57%), for p21 in 89 tumors (51%), and for mdm2 in only 16 tumors (9%). The only association found between immunostaining for the three antibodies was that most mdm2-positive tumors had positive p21 expression. Tumor mapping of regional immunostaining showed no association between immunostaining for p53 and p21. In a proportional hazards analysis, no association was found between the results of immunostaining for the three antibodies and treatment outcome. Positive or negative expression of p53, p21, or mdm2, or combinations of these, was not associated with cancer specific mortality after cystectomy for bladder carcinoma. There was no association between immunostaining for p21 and p53, whereas positive immunostaining for mdm2 was observed in a minority of the tumors. These results indicate that, in addition to p21, p53, and mdm2, there are other oncoproteins and tumor suppressor proteins along the p53 pathway that are involved in tumor development and progression.


Relation of vascular growth factors with CT-derived measures of body fat distribution: the Framingham Heart Study.
Visceral adiposity is associated with metabolic risk. Given that angiogenesis is a key feature of adipogenesis, variation in the association of levels of circulating vascular growth factors (and their soluble receptors) with distinct body fat compartments may explain differences in the systemic pathogenicity of regional fat depots. Four body fat compartments [visceral adipose tissue (VAT), sc adipose tissue (SAT), thoracic periaortic fat, and pericardial fat] derived from computed tomography were related to serum concentrations of vascular endothelial growth factor (VEGF), the soluble VEGF receptor (fms-like tyrosine kinase-1), hepatocyte growth factor (HGF), and angiopoietin-2 and its soluble receptor (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2 sTie-2) in 1806 Framingham Heart Study participants (mean age 44.9 yr, 44.5% women). In multivariable models, we observed positive associations between several fat compartments and VEGF and HGF levels. The magnitude of the associations were similar for VAT, SAT, and periaortic fat. We observed effect modification by sex. A stronger association was observed between VAT and HGF levels in women; higher VAT and periaortic fat were jointly associated with higher HGF concentrations (P=0.02 and P=0.051, respectively). In women within the highest tertile of VAT, HGF levels significantly increased with higher periaortic fat (P=0.0005). In our large community-based sample, greater adiposity was associated with higher circulating growth factor levels in general. Additional studies are warranted to confirm the stronger association of VAT and periaortic fat with HGF in women and to examine its potential contribution to the sex-related differences in cardiometabolic risk.


Too much interference: injection of double-stranded RNA has nonspecific effects in the zebrafish embryo.
We have investigated the ability of double-stranded RNA (dsRNA) to inhibit gene expression in a vertebrate, the zebrafish, Danio rerio. Injection of dsRNA corresponding to the T-box gene tbx16/spadetail (spt) into early wild-type embryos caused a rapid and dramatic loss of tbx16/spt mRNA in the blastula. mRNAs from the papc, tbx6, and gata1 genes, which depend on tbx16/spt function for their expression, were reduced, apparently mimicking the spt mutant phenotype. However, mRNAs from a number of genes that are unaffected by the spt mutation, such as beta catenin, stat3, and no tail, were also lost, indicating that the "interference" effect of tbx16/spt dsRNA was not restricted to the endogenous tbx16/spt mRNA. We compared the effects of injecting dsRNA from the zebrafish tbx16/spadetail, nieuwkoid/bozozok, and Brachyury/no tail genes with dsRNA from the bacterial lacZ gene. In each case the embryos displayed a variable syndrome of abnormalities at 12 and 24 h postfertilization. In blind studies, we could not distinguish between the effects of the various dsRNAs. Consistent with a common effect of dsRNA, regardless of sequence, injection of dsRNA from the lacZ gene was likewise effective in strongly reducing tbx16/spt and beta catenin mRNA in the blastula. These findings indicate that, despite published reports, the current methodology of double-stranded RNA interference is not a practical technique for investigating zygotic gene function during early zebrafish development.


Monoclonal anti-HBs antibodies radioimmunoassay and serum HBV-DNA hybridization as diagnostic tools of HBV infection: relative prevalence among HBsAg-negative alcoholics, patients with chronic hepatitis or hepatocellular carcinomas and blood donors.
Anti-HBs monoclonal antibodies radioimmunoassay (m-RIA) and HBV-DNA hybridization techniques were used to detect HBs antigen (HBsAg)--associated determinants (evidence of HBV on-going infection) and HBV-DNA sequences (evidence of viral multiplication) in the serum samples of 479 patients who were HBsAg negative by standard solid-phase radioimmunoassay. They included 128 alcoholics, 104 patients with chronic hepatitis, fifty-four with an hepatocellular carcinoma, 100 with coagulation disorders and ninety-three blood donors. The aim of this study was the comparison in these populations of the prevalence of the various HBV markers. m-RIA detected HBsAg-associated determinants in 1% of blood donors, 3% of coagulation disorders, 3.1% of the alcoholics, 21.1% of chronic hepatitis and 16.6% of hepatocellular carcinoma; hybridization identified HBV-DNA sequences in 0.9%, 2.2%, 10.9%, 9.6% and 5.5% of these cases, respectively. The combined prevalence of both markers of an on-going HBV infection (with or without viral multiplication) was 14.16%, 26.9% and 22.2% in the latter groups, respectively, as compared with only 3% in patients with coagulation disorders and 2.1% of blood donors. These results confirm the frequency of HBV or HBV-related virus infection in alcoholics, in chronic hepatitis and hepatocellular carcinomas, despite the absence of HBsAg by standard RIA (or even of any other usual marker); this gives further evidence for variations in the expression of HBV infection. A high and quite similar prevalence of usual serum markers and hybridization results was observed in the alcoholics and in the patients with chronic hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)


Genetic risk of Parkinson's disease in the general population.
We investigated whether a risk score based on genetic risk variants for Parkinson's disease (PD) is associated with the risk and improves prediction of incident PD, and whether the risk score is associated with basic activities of daily living (BADL) in healthy individuals. Within the population-based Rotterdam Study, we genotyped 26 independent risk variants for PD and constructed a genetic risk score in 7167 participants who were free of parkinsonism and dementia at baseline (1990 or 2000). Participants were followed for a maximum of twenty years for the onset of parkinsonism, dementia or death until January 1, 2011 (median follow-up 12.1 years). We studied the relationship between the genetic risk score and incident PD with adjustment for age, sex, smoking and parental history. In an independent sample of 2997 persons free of parkinsonism and dementia, we studied whether the PD risk score was associated with impaired BADL. During follow-up (median 12.1 years), 99 persons were diagnosed with incident PD. The genetic risk score was associated with incident PD (hazard ratio per standard deviation risk 1.25 [95% confidence interval = 1.02; 1.55]), but did not substantially improve prediction (change in C-statistic 0.687 [0.628; 0.745] to 0.698 [0.635; 0.760], ΔC = 0.011 [-0.011; 0.033]). The genetic risk score was associated with a higher probability of any impairment in BADL (odds ratio = 1.11 [1.00; 1.23]). Genetic variants for PD are associated with the risk of incident PD in the general population and with impairment in daily functioning in individuals without clinical parkinsonism, but do not improve the clinical prediction of PD. However, we were probably underpowered to detect a small improvement in PD prediction.


Accuracy of MRI-guided stereotactic thalamic functional neurosurgery.
Our goal was to evaluate the accuracy of stereotactic technique using MRI in thalamic functional neurosurgery. A phantom study was designed to estimate errors due to MRI distortion. Stereotactic mechanical accuracy was assessed with the Suetens-Gybels-Vandermeulen (SGV) angiographic localiser. Three-dimensional MRI reconstructions of 86 therapeutic lesions were performed. Their co-ordinates were corrected from adjustments based on peroperative electrophysiological data and compared to those planned. MR image distortion (maximum: 1 mm) and chemical shift of petroleum oil-filled localiser rods (2.2 mm) induced an anterior target displacement of 2.6 mm (at a field strength of 1.5 T, frequency encoding bandwidth of 187.7 kHz, on T1-weighted images). The average absolute error of the stereotactic material was 0.7 mm for anteroposterior (AP), 0.5 mm for mediolateral (ML) and 0.8 mm for dorsoventral (DV) co-ordinates (maximal absolute errors: 1.6 mm, 2.2 mm and 1.7 mm, respectively; mean euclidean error: 1 mm). Three-dimensional MRI reconstructions showed an average absolute error of 0.8 mm, 0.9 mm and 1.9 mm in AP, ML and DV co-ordinates, respectively (maximal absolute errors: 2.4 mm, 2.7 mm and 5.7 mm, respectively; mean euclidean error: 2.3 mm). MRI distortion and chemical-shift errors must be determined by a phantom study and then compensated for. The most likely explanation for an average absolute error of 1.9 mm in the DV plane is displacement of the brain under the pressure of the penetrating electrode. When this displacement is corrected for by microelectrode recordings and stimulation data, MRI offers a high degree of accuracy and reliability for thalamic stereotaxy.


Erythema after cutaneous laser resurfacing using a porcine model.
To measure and compare postoperative erythema after laser cutaneous resurfacing using 2 carbon dioxide laser systems and varying postoperative treatment methods. Carbon dioxide laser systems are used as cutaneous resurfacing tools. The continuous-wave lasers have been associated with postoperative erythema, but the short-pulsed lasers reportedly result in less postoperative erythema because of shorter pulse durations. Although subjective evaluations of results have been published, a side-by-side comparison with digital photography has not been performed. Furthermore, postoperative treatment varies among physicians, and objective data about this treatment are scarce. To compare postoperative erythema, we created 240 resurfacing wounds on 8 piglets with continuous-wave and short-pulsed lasers, using the manufacturers' suggested settings. By using photography and computed color analysis, we measured the resultant erythema after 1, 3, and 5 laser passes at days 0, 1, 3, 5, 7, and 14. Tissue samples were obtained for histological analysis on days 0, 3, 7, and 14. We compared the resolution of erythema after postoperative treatment with petroleum jelly (Vaseline), a wound dressing (Vigilon), partially hydrogenated vegetable oil (Crisco), or a combination drug, bacitracin zinc-neomycin sulfate-polymyxin B sulfate on the wounds. The short-pulsed carbon dioxide laser resulted in an average of 22% less erythema compared with the continuous-wave laser (P<.001). No statistically significant difference in erythema was found among the postoperative treatment methods (P>.10). Compared with the continuous-wave laser, the short-pulsed carbon dioxide laser results in less postoperative erythema. However, the type of postoperative treatment has little, if any, beneficial effect for reducing erythema.


Everything depends on everything else.
In physics the concept of entanglement is well established and it has become increasingly apparent that all levels of biological organization (communities, organisms, cells, metabolism) consist of mosaics of interactive networks. There is a universe of bioactive microbial chemicals that have so far only been considered for their therapeutic applications; for example, the environmental roles of antibiotics have been little investigated. At sub-inhibitory concentrations, so-called antibiotics have been shown to modulate bacterial functions in subtle ways; they behave more like signals than toxins. It is proposed that networks of microbial cell signalling are primarily based on the interactions of low molecular weight compounds with macromolecular receptors; studies of the nature of these signals will reveal important information on the functions of microbial communities.


Effects of single low-temperature sauna bathing in patients with severe motor and intellectual disabilities.
We have previously reported that thermal vasodilation following warm-water bathing and low-temperature sauna bathing (LTSB) at 60 degrees C for 15 min improves the cardiac function in patients with congestive heart failure. Through a comparative before-and-after study, we studied the hemodynamic and clinical effects of single exposure to LTSB in cerebral palsy (CP) patients who usually suffer from chilled extremities and low cardiac output. The study population comprised 16 patients ranging between 19 and 53 years with severe motor and intellectual disabilities. Noninvasive methods were used to estimate the systemic and peripheral circulatory changes before and after LTSB. Using blood flow velocity analysis, the pulsatile and resistive indexes of the peripheral arteries of the patients' lower limbs were calculated. Following LTSB, the patients' deep body temperature increased significantly by 1 degrees C. Their heart rates increased and blood pressure decreased slightly. The total peripheral resistance decreased by 11%, and the cardiac output increased by 14%. There was significant improvement in the parameters that are indicative of the peripheral circulatory status, including the skin blood flow, blood flow velocity, pulsatile index, and resistive index. Numbness and chronic myalgia of the extremities decreased. There were no adverse side effects. Thus, it can be concluded that LTSB improves the peripheral circulation in CP patients.


Prevalence and predictors of culprit plaque rupture at OCT in patients with coronary artery disease: a meta-analysis.
The prevalence of plaque rupture at the culprit lesion identified by optical coherence tomography (OCT) in different clinical subset of patients undergoing coronary angiography and its clinical predictors remain to be defined. All studies including patients with OCT evaluation of the culprit coronary plaque were included. The prevalence of culprit plaque rupture (CPR) and thin-cap fibro-atheroma (TCFA) were the primary endpoints. The factors associated with these findings were studied in a subset of patients with different clinical presentations [ST-elevation myocardial (STEMI) vs. nonST-elevation myocardial infarction (NSTEMI) vs. unstable angina (UA) vs. stable angina pectoris (SAP)]. One hundred and fifty citations were initially appraised at the abstract level and 23 full-text studies were assessed. The mean prevalence of CPR and TCFA was 48.1% (40.5-55.8) and 48.7% (37.4-60.1), respectively. The prevalence of CPR and TCFA were higher in STEMI (70.4 and 76.6%) than in NSTEMI (55.6 and 56.3%) and UA (39.1 and 52.9%) or SAP (6.2 and 22.8%). In the overall population at meta-regression analysis, TCFA and current smoking were the only predictors of CPR (B 3.6:2.0-5.1, P < 0.001 and 0.06:0.02-0.1, P = 0.002, respectively). The factors associated with CPR were different depending on clinical presentation. Hypertension was the only clinical predictor for STEMI (B 3.3: 1.2.-5.3 P = 0.001), while advanced age (B 0.12: 0.02-0.22, P = 0.021), diabetes mellitus (B 0.04: 0.01-0.08, P = 0.012), and hyperlipidaemia (B 0.07:0.02-0.11, P = 0.005) were the predictors in NSTEMI and UA. No clinical predictor was found in SA. Our analysis showed high rates of CPR and TCFA detected by OCT in CAD patients, especially in those with ACS, although their prevalence is not negligible in stable patients. TCFA seems to be a strong predictor of CPR in all the ACS scenarios.


Epidermal growth factor-mediated inhibition of neurotransmitter glutamate release from rat forebrain synaptosomes.
We investigated the possibility that receptor tyrosine kinases are involved in modulating neurotransmitter release from isolated nerve terminals. We examined the effects of epidermal growth factor on the release of neurotransmitter glutamate evoked from rat forebrain synaptosomes by KCI and 4-aminopyridine. We detected a significant inhibition of the Ca2+-dependent component of release. This effect appears to be mediated by a reduction in the depolarization-evoked increase in cytosolic free calcium levels, in the absence of significant effects on the plasma membrane potential. On depolarization, a Ca2+-dependent increase was observed in the phosphotyrosine content of bands at molecular masses of approximately 107 and approximately 40 kDa. The addition of epidermal growth factor before depolarization induced a significant phosphorylation of the growth factor receptor in the absence of detectable changes in the phosphotyrosine pattern of total synaptosomal proteins, suggesting that phosphorylation of a minor protein is responsible for the epidermal growth factor-mediated inhibition of glutamate release.


Persistent Muscle Fiber Regeneration in Long Term Denervation. Past, Present, Future.
Despite the ravages of long term denervation there is structural and ultrastructural evidence for survival of muscle fibers in mammals, with some fibers surviving at least ten months in rodents and 3-6 years in humans. Further, in rodents there is evidence that muscle fibers may regenerate even after repeated damage in the absence of the nerve, and that this potential is maintained for several months after denervation. While in animal models permanently denervated muscle sooner or later loses the ability to contract, the muscles may maintain their size and ability to function if electrically stimulated soon after denervation. Whether in mammals, humans included, this is a result of persistent de novo formation of muscle fibers is an open issue we would like to explore in this review. During the past decade, we have studied muscle biopsies from the quadriceps muscle of Spinal Cord Injury (SCI) patients suffering with Conus and Cauda Equina syndrome, a condition that fully and irreversibly disconnects skeletal muscle fibers from their damaged innervating motor neurons. We have demonstrated that human denervated muscle fibers survive years of denervation and can be rescued from severe atrophy by home-based Functional Electrical Stimulation (h-bFES). Using immunohistochemistry with both non-stimulated and the h-bFES stimulated human muscle biopsies, we have observed the persistent presence of muscle fibers which are positive to labeling by an antibody which specifically recognizes the embryonic myosin heavy chain (MHCemb). Relative to the total number of fibers present, only a small percentage of these MHCemb positive fibers are detected, suggesting that they are regenerating muscle fibers and not pre-existing myofibers re-expressing embryonic isoforms. Although embryonic isoforms of acetylcholine receptors are known to be re-expressed and to spread from the end-plate to the sarcolemma of muscle fibers in early phases of muscle denervation, we suggest that the MHCemb positive muscle fibers we observe result from the activation, proliferation and fusion of satellite cells, the myogenic precursors present under the basal lamina of the muscle fibers. Using morphological features and molecular biomarkers, we show that severely atrophic muscle fibers, with a peculiar cluster reorganization of myonuclei, are present in rodent muscle seven-months after neurectomy and in human muscles 30-months after complete Conus-Cauda Equina Syndrome and that these are structurally distinct from early myotubes. Beyond reviewing evidence from rodent and human studies, we add some ultrastructural evidence of muscle fiber regeneration in long-term denervated human muscles and discuss the options to substantially increase the regenerative potential of severely denervated human muscles not having been treated with h-bFES. Some of the mandatory procedures, are ready to be translated from animal experiments to clinical studies to meet the needs of persons with long-term irreversible muscle denervation. An European Project, the trial Rise4EU (Rise for You, a personalized treatment for recovery of function of denervated muscle in long-term stable SCI) will hopefully follow.


Accurate brain age prediction with lightweight deep neural networks.
Deep learning has huge potential for accurate disease prediction with neuroimaging data, but the prediction performance is often limited by training-dataset size and computing memory requirements. To address this, we propose a deep convolutional neural network model, Simple Fully Convolutional Network (SFCN), for accurate prediction of brain age using T1-weighted structural MRI data. Compared with other popular deep network architectures, SFCN has fewer parameters, so is more compatible with small dataset size and 3D volume data. The network architecture was combined with several techniques for boosting performance, including data augmentation, pre-training, model regularization, model ensemble and prediction bias correction. We compared our overall SFCN approach with several widely-used machine learning models. It achieved state-of-the-art performance in UK Biobank data (N = 14,503), with mean absolute error (MAE) = 2.14y in brain age prediction and 99.5% in sex classification. SFCN also won (both parts of) the 2019 Predictive Analysis Challenge for brain age prediction, involving 79 competing teams (N = 2,638, MAE = 2.90y). We describe here the details of our approach, and its optimisation and validation. Our approach can easily be generalised to other tasks using different image modalities, and is released on GitHub.


Latent polyglandular autoimmune syndrome type 2 case diagnosed during a shock manifestation.
There are many types of polyglandular autoimmune syndrome (PAS). PAS type 2 is the most common type among adults. For PAS type 2 (PAS-2) diagnosis, detection of Addison's disease with autoimmune thyroid disease and/or type 1 diabetes mellitus are required. Premature ovarian insufficiency, pernicious anemia, vitiligo, alopecia, myasthenia gravis, celiac disease and autoimmune diabetes insipidus may be comorbidities of this condition. Contrary to the common belief, latent PAS is more common than the manifest forms. Here, we present a PAS-2 case diagnosed via adrenal crisis. At the time of diagnosis, the case was observed to have thyroid, adrenal and ovarian involvement. Therefore, PAS-2 and possible immunologic disorders were discussed.


Advancing Research on Care Needs and Supportive Approaches for Persons With Dementia: Recommendations and Rationale.
The first National Research Summit on Care, Services, and Supports for Persons with Dementia and Their Caregivers was held on October 16-17, 2017, at the National Institutes of Health. In this paper, participants from the Summit Session on Research on Care Needs and Supportive Approaches for Persons with Dementia summarize the state of the science, identify gaps in knowledge, and offer recommendations to improve science and practice in long-term care. Recommendations cover 4 areas focused on persons living with dementia: (1) symptoms (behavioral and psychological symptoms of dementia, function, cognition, and sleep); (2) dementia care settings (physical and social environments, home, and residential care); (3) living with dementia (living well with dementia, living alone with dementia, and living with dementia and intellectual and developmental disabilities); and (4) technology as a cross-cutting theme. The participants identify 10 of the most pressing research issues based on the findings from their collective papers. Final Summit recommendations included those presented by session participants and will be used to advise federal agencies and other organizations that fund research.


Venous angioplasty in multiple sclerosis: neurological outcome at two years in a cohort of relapsing-remitting patients.
An open study was conducted with the aim of reporting long-term clinical outcome of endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) in patients with multiple sclerosis (MS). Twenty-nine patients with clinically definite relapsing-remitting MS underwent percutaneous transluminal angioplasty for CCSVI, outside a clinical relapse. All the patients were regularly observed over at least two years before the first endovascular treatment and for at least two years after it (mean post-procedure follow up 30.6±6.1 months). The following clinical outcome measures were used: annual relapse rate and Expanded Disability Status Scale (EDSS) score. All the patients were observed intensively (mean 6 hours) on the day of the endovascular treatment to monitor for possible complications (bleeding, shock, heart attack, death). We compared the annual relapse rate before and after treatment (in the two years before and the two years after the first endovascular treatment) and the EDSS score recorded two years before versus two years after the treatment. Overall, 44 endovascular procedures were performed in the 29 patients, without complications. Thirteen of the 29 patients (45%) underwent more than one treatment session because of venous re-stenosis: 11 and two patients underwent two and three endovascular treatments respectively. The annual relapse rate of MS was significantly lower post-procedure (0.45±0.62 vs 0.76±0.99; p=0.021), although it increased in four patients. The EDSS score two years after treatment was significantly lower compared to the EDSS score recorded at the examination two years before treatment (1.98±0.92 vs 2.27±0.93; p=0.037), although it was higher in four patients. Endovascular treatment of concurrent CCSVI seems to be safe and repeatable and may reduce annual relapse rates and cumulative disability in patients with relapsing-remitting MS. Randomized controlled studies are needed to further assess the clinical effects of endovascular treatment of CCSVI in MS.


Neuronal density in the human retinal ganglion cell layer from 16-77 years.
Literature assessing whether or not neurons (retinal ganglion cells and displaced amacrine cells) are lost from the retinal ganglion cell layer in mammals with age is still controversial, some studies finding a decrease in cell density and others not. To date there have been no studies estimating the total number of neurons in the retinal ganglion cell layer of humans throughout life. Recent studies have concentrated on the macular region and examined cell densities, which are reported to decrease during aging. In a study of the human retinal pigment epithelium (RPE), we showed that, while RPE cell number does not change, cell density increases significantly in central temporal retina (macular region) as the retina ages. We speculated that the increase in density represents a "drawing together" of the retinal sheet to maintain high cell densities, in this region of the neural retina, in the face of presumed cell loss from the ganglion cell layer due to aging. Here, therefore, we have sampled the entire ganglion cell layer of the human retina and estimated total neuron numbers in 12 retinae aged from 16 to 77 years. Human retinae, fixed in formalin, were obtained from the Queensland Eye Bank and whole-mounted, ganglion cell layer uppermost. The total number of neurons was lower in the older than younger retinae and neuronal density was lower in most retinal regions in older retinae. Retinal area increased with age and neuronal density fell throughout the retina with a mean reduction of 0.53% per year. However, the percentage reduction in density was much lower for the macular region, with a value of 0.29% per year. It is possible that this lesser reduction in cell density in the macula is a result of the drawing together of the retinal sheet in this region as we speculated from RPE data.


Neurodevelopmental Outcome of Extremely Low Birth Weight Infants Fed an Exclusive Human Milk Diet Is Not Affected by Growth Velocity.
Background: An exclusive human milk (EHM) diet in extremely low birth weight (ELBW) infants (birth weight ≤1,000 g) is linked to an increased likelihood of extrauterine growth restriction (EUGR, weight <10% at discharge). Past studies associated EUGR with worse neurodevelopmental (ND) outcomes; however, its impact when an EHM diet is used is unknown. Objective: Determine whether EUGR adversely affects 2-year ND outcomes of ELBW infants fed an EHM diet. Secondary aims were to compare short-term morbidities and growth through 2 years corrected age (CA). Materials and Methods: Prospective cohort study of ELBW infants fed an EHM diet until 34 weeks corrected gestational age and assessed at 2 years CA. ND outcomes between EUGR and non-EUGR infants were compared using the Bayley Scales of Infant Development 3rd Ed (BSID-III). Results: Eighty-one ELBW infants survived, 44 were seen for follow-up, and 16 (36%) were EUGR. Baseline characteristics and Neonatal Intensive Care Unit (NICU) morbidities were similar. There were no statistically significant differences (median [25-75%]) between EUGR and non-EUGR groups in cognition, (90 [80-99] versus 95 [90-104]), language (84 [68-105] versus 89 [75-100]), or motor composite scores (87 [74-96] versus 91 [88-96]). Weight z-scores during NICU stay dropped in both groups, more pronounced for the EUGR infants. There was no difference in linear or head growth. Conclusion: In our institution, ND outcomes at 2 years CA for ELBW infants fed an EHM diet were similar regardless of EUGR status. This suggests a neuroprotective effect of EHM diet in the ELBW population, despite weight gain velocity during NICU stay.


'They're not racist ...' prejudice denial, mitigation and suppression in dialogue.
Social scientific work on the suppression, mitigation or denial of prejudiced attitudes has tended to focus on the strategic self-presentation and self-monitoring undertaken by individual social actors on their own behalf. In this paper, we argue that existing perspectives might usefully be extended to incorporate three additional considerations. First, that social actors may, on some occasions, act to defend not only themselves, but also others from charges of prejudice. Second, that over the course of any social encounter, interactants may take joint responsibility for policing conversation and for correcting and suppressing the articulation of prejudiced talk. Third, that a focus on the dialogic character of conversation affords an appreciation of the ways in which the status of any particular utterance, action or event as 'racist' or 'prejudiced' may constitute a social accomplishment. Finally, we note the logical corollary of these observations - that in everyday life, the occurrence of 'racist discourse' is likely to represent a collaborative accomplishment, the responsibility for which is shared jointly between the person of the speaker and those other co-present individuals who occasion, reinforce or simply fail to suppress it.


A prospective study of the effects of optimism on adolescent health risks.
The promotion of optimism has been widely advocated for children and adolescents, but epidemiologic data to support this approach are scant. This was a 3-wave longitudinal study of health and social development in younger adolescents from 3 Australian states. The 5634 student participants, initially aged 12 to 14 years, were assessed for optimistic thinking style, emotional problems, substance use, and antisocial behaviors. Cross-sectional associations between optimism and each of the study outcomes were strongly protective but tended to differ according to gender in extent. In prospective analyses of the onset of new cases of each study outcome, protective associations were weaker. Those in the highest optimism quartile had risks for depressive symptoms that were reduced by almost half (odds ratio: 0.54 [95% confidence interval: 0.42-0.70]) compared with those in the lowest category. No effect was seen in prevention of anxiety symptoms after adjustment for other aspects of psychological style. In predicting the onset of heavy substance use and antisocial behavior, high optimism had modest protective effects. Optimistic thinking style is somewhat protective against adolescent health risks; the clearest effects are seen against depressive symptoms. Promoting optimism along with other aspects of psychological and emotional style has a role in mental health promotion that is likely to be enhanced if an intervention also addresses risk and protective factors in an adolescent's social context.


Phytoestrogen Metabolism by Adult Human Gut Microbiota.
Phytoestrogens are plant-derived polyphenols with a structure similar to human estrogens. The three main groups of phytoestrogens, isoflavones, ellagitannins, and lignans, are transformed into equol, urolithins, and enterolignans, respectively, by bacteria. These metabolites have more estrogenic/antiestrogenic and antioxidant activities than their precursors, and they are more bioavailable. The aim of this study was to analyze the metabolism of isoflavones, lignans and ellagitannins by gut microbiota, and to study the possible correlation in the metabolism of these three groups of phytoestrogens. In vitro fermentation experiments were performed with feces samples from 14 healthy adult volunteers, and metabolite formation was measured by HPLC-PAD and HPLC-ESI/MS. Only the microbiota of one subject produced equol, while most of them showed production of O-desmethylangolensin (O-DMA). Significant inter-subject differences were observed in the metabolism of dihydrodaidzein and dihydrogenistein, while the glucoside isoflavones and their aglycones showed less variability, except for glycitin. Most subjects produced urolithins M-5 and E. Urolithin D was not detected, while uroltithin B was found in half of the individuals analyzed, and urolithins A and C were detected in two and four subjects, respectively. Enterolactone was found in all subjects, while enterodiol only appeared in five. Isoflavone metabolism could be correlated with the metabolism of lignans and ellagitannins. However, the metabolism of ellagitannins and lignans could not be correlated. This the first study where the metabolism of the three groups together of phytoestrogen, isoflavones, lignans, and ellagitannins by gut microbiota is analyzed.


Psychophysical and neuroimaging responses to moving stimuli in a patient with the Riddoch phenomenon due to bilateral visual cortex lesions.
Patients with injury to early visual cortex or its inputs can display the Riddoch phenomenon: preserved awareness for moving but not stationary stimuli. We provide a detailed case report of a patient with the Riddoch phenomenon, MC. MC has extensive bilateral lesions to occipitotemporal cortex that include most early visual cortex and complete blindness in visual field perimetry testing with static targets. Nevertheless, she shows a remarkably robust preserved ability to perceive motion, enabling her to navigate through cluttered environments and perform actions like catching moving balls. Comparisons of MC's structural magnetic resonance imaging (MRI) data to a probabilistic atlas based on controls reveals that MC's lesions encompass the posterior, lateral, and ventral early visual cortex bilaterally (V1, V2, V3A/B, LO1/2, TO1/2, hV4 and VO1 in both hemispheres) as well as more extensive damage to right parietal (inferior parietal lobule) and left ventral occipitotemporal cortex (VO1, PHC1/2). She shows some sparing of anterior occipital cortex, which may account for her ability to see moving targets beyond ~15 degrees eccentricity during perimetry. Most strikingly, functional and structural MRI revealed robust and reliable spared functionality of the middle temporal motion complex (MT+) bilaterally. Moreover, consistent with her preserved ability to discriminate motion direction in psychophysical testing, MC also shows direction-selective adaptation in MT+. A variety of tests did not enable us to discern whether input to MT+ was driven by her spared anterior occipital cortex or subcortical inputs. Nevertheless, MC shows rich motion perception despite profoundly impaired static and form vision, combined with clear preservation of activation in MT+, thus supporting the role of MT+ in the Riddoch phenomenon.


Aging in man. Linear increase of a novel T cell subset defined by antiganglioside monoclonal antibody 3G5.
A new human T cell subset defined by antineuronal ganglioside mAb 3G5 increases linearly with advancing age in man. The percentage of circulating 3G5+ T cells in 21 normal individuals, quantitated by cytofluorograph analysis, increases linearly from age 7 (23-30%) to age 84 (58%) (r = 0.85, p less than 0.001). The antigen on T cells has the biochemical properties of a ganglioside that migrates between GM1 and GM2 ganglioside markers on TLC. The 3G5 subset represents the first T cell subset that reflects aging in man.


Preoperative predictors of survival in patients with Thoratec ventricular assist devices as a bridge to heart transplantation. Thoratec Ventricular Assist Device Principal Investigators.
Approximately two-thirds of patients implanted with ventricular assist devices recover sufficiently to requalify for heart transplantation, and the other one-third die of complications that are often secondary to delayed ventricular assist device implantation and subsequent end-organ failure. To determine whether any preoperative predictors of survival exist, univariate statistics and multivariate stepwise logistic regression analysis were performed on pre-ventricular assist device demographics, hemodynamics, and blood chemistry in 186 patients receiving Thoratec ventricular assist devices (Thoratec Laboratories Corp., Berkeley, Calif.) while awaiting transplantation. The duration of circulatory support averaged 19.6 days (maximum, 226 days). One hundred thirty-seven patients (74%) received biventricular support, 47 received isolated left ventricular assist devices, and two received right ventricular assist devices. The average blood flow was 5.0 +/- 0.9 L/min. One hundred eighteen patients (63%) ultimately received heart transplants, of whom 96 patients were discharged. Age, gender, weight, and diagnosis were not related to survival, nor were preoperative cardiac index, pulmonary capillary wedge pressure, intraaortic balloon pumps, or cardiac arrests. Pre-ventricular assist device creatinine levels (p = 0.24) and total bilirubin levels (p = 0.09) were not significant, but blood urea nitrogen level (p = 0.02) and previous operations (p = 0.05) were related to survival, using univariate techniques. Patients with cardiac operations more than 30 days previously had the lowest survival-to-transplantation (39%) compared with patients with no previous operations (67%) or operations within the previous 30 days (61%). Blood urea nitrogen level was the only parameter found to be significant (p = 0.016) in a multivariate model.(ABSTRACT TRUNCATED AT 250 WORDS)


Glucocorticoids suppress macrophage migration inhibitory factor (MIF) expression in a cell-type-specific manner.
MIF is a potent proinflammatory cytokine involved in inflammatory arthritis. Glucocorticoids (GC) have been reported to induce secretion of MIF in rodent cells, and as MIF counteracts the anti-inflammatory effects of GC, this has implications for human inflammatory disease. Transient transfection studies showed that the MIF promoter was repressed by dexamethasone (Dex) (10 nM) in CEM C7A cells, with up to 50% suppression by 100 nM. However, there was no regulation of the promoter by GC in A549 cells. We also found that subnanomolar concentrations of Dex suppressed MIF secretion, measured by ELISA, by 80% in both human T lymphoblasts (CEM C7A) and human lung epithelial cells (A549). Endogenous MIF mRNA was also repressed by GC in CEM C7A cells, measured both by Northern blot and quantitative RT-PCR assays, but there was no such regulation in A549 cells. This suggests that GC affects translation rather than transcription of MIF in A549 cells. These results contradict earlier results with the rat cell line RAW 264.7. Therefore, we analysed MIF secretion from RAW 264.7 cells but found no GC effect on secretion. Understanding how GC regulates MIF in a cell-type-dependent manner may give insights into GC-refractory human inflammatory diseases.


Ozone and water-vapor measurements by Raman lidar in the planetary boundary layer: error sources and field measurements.
A new lidar instrument has been developed to measure tropospheric ozone and water vapor at low altitude. The lidar uses Raman scattering of an UV beam from atmospheric nitrogen, oxygen, and water vapor to retrieve ozone and water-vapor vertical profiles. By numerical simulation we investigate the sensitivity of the method to both atmospheric and device perturbations. The aerosol optical effect in the planetary boundary layer, ozone interference in water-vapor retrieval, statistical error, optical cross talk between Raman-shifted channels, and optical cross talk between an elastically backscattered signal in Raman-shifted signals and an afterpulse effect are studied in detail. In support of the main conclusions of this model study, time series of ozone and water vapor obtained at the Swiss Federal Institute of Technology in Lausanne and during a field campaign in Crete are presented. They are compared with point monitor and balloon sounding measurements for daytime and nighttime conditions.


Analysis of Anti-RNA Polymerase III Antibody-positive Systemic Sclerosis and Altered GPATCH2L and CTNND2 Expression in Scleroderma Renal Crisis.
Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) strongly associated with anti-RNA polymerase III antibody (ARA) autoantibodies. We investigated genetic susceptibility and altered protein expression in renal biopsy specimens in ARA-positive patients with SRC. ARA-positive patients (n = 99) with at least 5 years' follow-up (49% with a history of SRC) were selected from a well characterized SSc cohort (n = 2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, 9 single-nucleotide polymorphisms (SNP) were chosen for validation in a separate cohort of 256 ARA-positive patients (40 with SRC). Immunostaining of tissue sections from SRC or control kidney was used to quantify expression of candidate proteins based upon genetic analysis of the discovery cohort. Analysis of 641,489 SNP suggested association of POU2F1 (rs2093658; P = 1.98 × 10-5), CTNND2 (rs1859082; P = 5.58 × 10-5), HECW2 (rs16849716; P = 1.2 × 10-4), and GPATCH2L (rs935332; P = 4.92 × 10-5) with SRC. Further, the validation cohort showed an association between rs935332 within the GPATCH2L region, with SRC (P = 0.025). Immunostaining of renal biopsy sections showed increased tubular expression of GPATCH2L (P = 0.026) and glomerular expression of CTNND2 (P = 0.026) in SRC samples (n = 8) compared with normal human kidney controls (n = 8), despite absence of any genetic replication for the associated SNP. Increased expression of 2 candidate proteins, GPATCH2L and CTNND2, in SRC compared with control kidney suggests a potential role in pathogenesis of SRC. For GPATCH2L, this may reflect genetic susceptibility in ARA-positive patients with SSc based upon 2 independent cohorts.


Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression.
Tumor necrosis factor-α (TNF-α) elicits its biological activities through activation of TNF receptor 1 (TNFR1, also known as p55) and TNFR2 (also known as p75). The activities of both receptors are required for the TNF-α-induced proinflammatory response. The adaptor protein TNFR-associated factor 2 (TRAF2) is critical for either p55- or p75-mediated activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, as well as for target gene expression. We identified nonmuscle myosin II (myosin) as a binding partner of p75. TNF-α-dependent signaling by p75 and induction of target gene expression persisted substantially longer in cells deficient in myosin regulatory light chain (MRLC; a component of myosin) than in cells replete in myosin. In resting endothelial cells, myosin was bound constitutively to the intracellular region of p75, a region that overlaps with the TRAF2-binding domain, and TNF-α caused the rapid dissociation of myosin from p75. At early time points after exposure to TNF-α, p75 activated Rho-associated kinase 1 (ROCK1). Inhibition of ROCK1 activity blocked TNF-α-dependent phosphorylation of MRLC and the dissociation of myosin from p75. ROCK1-dependent release of myosin was necessary for the TNF-α-dependent recruitment of TRAF2 to p75 and for p75-specific activation of NF-κB and MAPK signaling. Thus, our findings have revealed a previously uncharacterized, noncanonical regulatory function of myosin in cytokine signaling.