Symptoms and Well-Being in Older Hospitalized Patients with Cognitive Impairment, As Self-Reported and Reported in Patient Records: A Quantitative Exploratory Subgroup Analysis.
Given the aging population and the high prevalence of cognitive impairment in older hospitalized patients, it is essential to provide good fundamental care to these vulnerable patients, who easily might be affected by poor outcomes as delirium. Risk factors for delirium are, for example, cognitive impairment, old age, pain, and sleep deprivation. Different symptoms are often unidentified in hospitals, and associated with poor well-being, but this is rarely studied in older patients with cognitive impairment. The study aim was to examine symptoms and sense of well-being in older hospitalized patients with cognitive impairment, as self-reported and reported in patient records. Exploratory quantitative subgroup (n = 25) analysis of a point-prevalence study (n = 210). Inclusion criteria were age ≥65, and cognitive impairment. Data were collected through structured interviews, validated instruments, and patient records. Associations between well-being and symptoms, and concordance between the occurrence of self-reported symptoms and symptoms reported in patient records were analyzed. The patients reported severe and distressing symptoms that were sparsely reported (14%) in their records. As well were cognitive impairment, and the patients' own descriptions of their well-being. Some symptoms and the total symptom burden were associated with poor well-being. To our knowledge, this hypothesis-generating study is one of few studies that describe both symptoms and well-being as self-reported and reported in patient records, in vulnerable patients due to old age, cognitive impairment, and hospitalization. Despite the limited sample size, the results indicate that symptoms were more insufficient alleviated in these patients compared to patients with normal cognitive function in other studies. To our knowledge, this has not been shown previously. Additionally, patients' own experiences were sparsely reported in their records. A larger sample size and longitudinal design has the potential to determine if symptom alleviation differs between patients with and without cognitive impairment, and if a total symptom burden increases the risk of poor outcomes as delirium in vulnerable patients.


Predicting pathway cross-talks in ankylosing spondylitis through investigating the interactions among pathways.
Given that the pathogenesis of ankylosing spondylitis (AS) remains unclear, the aim of this study was to detect the potentially functional pathway cross-talk in AS to further reveal the pathogenesis of this disease. Using microarray profile of AS and biological pathways as study objects, Monte Carlo cross-validation method was used to identify the significant pathway cross-talks. In the process of Monte Carlo cross-validation, all steps were iterated 50 times. For each run, detection of differentially expressed genes (DEGs) between two groups was conducted. The extraction of the potential disrupted pathways enriched by DEGs was then implemented. Subsequently, we established a discriminating score (DS) for each pathway pair according to the distribution of gene expression levels. After that, we utilized random forest (RF) classification model to screen out the top 10 paired pathways with the highest area under the curve (AUCs), which was computed using 10-fold cross-validation approach. After 50 bootstrap, the best pairs of pathways were identified. According to their AUC values, the pair of pathways, antigen presentation pathway and fMLP signaling in neutrophils, achieved the best AUC value of 1.000, which indicated that this pathway cross-talk could distinguish AS patients from normal subjects. Moreover, the paired pathways of SAPK/JNK signaling and mitochondrial dysfunction were involved in 5 bootstraps. Two paired pathways (antigen presentation pathway and fMLP signaling in neutrophil, as well as SAPK/JNK signaling and mitochondrial dysfunction) can accurately distinguish AS and control samples. These paired pathways may be helpful to identify patients with AS for early intervention.


A large-scale field trial of thin-layer capping of PCDD/F-contaminated sediments: Sediment-to-water fluxes up to 5 years post-amendment.
The longer-term effect (3-5 y) of thin-layer capping on in situ sediment-to-surface water fluxes was monitored in a large-scale field experiment in the polychlorinated dibenzodioxin and dibenzofuran (PCDD/F) contaminated Grenlandfjords, Norway (4 trial plots of 10,000 to 40,000 m(2) at 30 to 100 m water depth). Active caps (designed thickness 2.5 cm) were established in 2 fjords, consisting of dredged clean clay amended with powdered activated carbon (PAC) from anthracite. These active caps were compared to 2 nonactive caps in one of the fjords (designed thickness 5 cm) consisting of either clay only (i.e., without PAC) or crushed limestone. Sediment-to-water PCDD/F fluxes were measured in situ using diffusion chambers. An earlier study showed that during the first 2 years after thin-layer capping, flux reductions relative to noncapped reference fields were more extensive at the fields capped with nonactive caps (70%-90%) than at the ones with PAC-containing caps (50%-60%). However, the present work shows that between 3 and 5 years after thin-layer capping, this trend was reversed and cap effectiveness in reducing fluxes was increasing to 80% to 90% for the PAC caps, whereas cap effectiveness of the nonactive caps decreased to 20% to 60%. The increasing effectiveness over time of PAC-containing "active" caps is explained by a combination of slow sediment-to-PAC mass transfer of PCDD/Fs and bioturbation by benthic organisms. The decreasing effectiveness of "nonactive" limestone and clay caps is explained by deposition of contaminated particles on top of the caps. The present field data indicate that the capping efficiency of thin active caps (i.e., enriched with PAC) can improve over time as a result of slow diffusive PCDD/F transfer from sediment to PAC particles and better mixing of the PAC by bioturbation.


BALB/c myeloma retroviruses: peptide mapping and immunological analysis of the pp12 structural protein.
We have compared the pp12 structural protein of the MO-21 and FL-1 BALB/c myeloma retroviruses with the pp12 of several prototype retroviruses. Chymotryptic peptide maps of 125I-labeled, immune-precipitated pp12 proteins revealed that the MO-21 and FL-1 proteins can be distinguished from one another. The MO-21 pp12 most closely resembled the NIH-xenotrophic virus pp12, and the FL-1 pp12 most closely resembled the pp12 of BV-2 and WN 1802 B. Competition radioimmunoassay studies showed that the MO-21 and FL-1 pp12 proteins are also antigenically distinct from one another and that both contain pp12 antigenic determinants of a xenotropic virus. These data support our proposal that these two BALB/c viruses contain a gag gene that was generated by recombination between endogenous eco- and xenotropic viral sequences.


Environmental and epigenetic regulation of Rider retrotransposons in tomato.
Transposable elements in crop plants are the powerful drivers of phenotypic variation that has been selected during domestication and breeding programs. In tomato, transpositions of the LTR (long terminal repeat) retrotransposon family Rider have contributed to various phenotypes of agronomical interest, such as fruit shape and colour. However, the mechanisms regulating Rider activity are largely unknown. We have developed a bioinformatics pipeline for the functional annotation of retrotransposons containing LTRs and defined all full-length Rider elements in the tomato genome. Subsequently, we showed that accumulation of Rider transcripts and transposition intermediates in the form of extrachromosomal DNA is triggered by drought stress and relies on abscisic acid signalling. We provide evidence that residual activity of Rider is controlled by epigenetic mechanisms involving siRNAs and the RNA-dependent DNA methylation pathway. Finally, we demonstrate the broad distribution of Rider-like elements in other plant species, including crops. Our work identifies Rider as an environment-responsive element and a potential source of genetic and epigenetic variation in plants.


"I have an evil child at my house": stigma and HIV/AIDS management in a South African community.
We examined the social roots of stigma by means of a case study of HIV/AIDS management among young people in a South African community (drawing from interviews, focus groups, and fieldworker diaries). We highlight the web of representations that sustain stigma, the economic and political contexts within which these representations are constructed, and the way in which they flourish in the institutional contexts of HIV/AIDS interventions. Stigma serves as an effective form of "social psychological policing" by punishing those who have breached unequal power relations of gender, generation, and ethnicity. We outline an agenda for participatory programs that promote critical thinking about stigma's social roots to stand alongside education and, where possible, legislation as an integral part of antistigma efforts.


Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings.
Considerable interest has been shown in the ability of caloric restriction (CR) to improve multiple parameters of health and to extend lifespan. CR is the reduction of caloric intake - typically by 20 - 40% of ad libitum consumption - while maintaining adequate nutrient intake. Several alternatives to CR exist. CR combined with exercise (CE) consists of both decreased caloric intake and increased caloric expenditure. Alternate-day fasting (ADF) consists of two interchanging days; one day, subjects may consume food ad libitum (sometimes equaling twice the normal intake); on the other day, food is reduced or withheld altogether. Dietary restriction (DR) - restriction of one or more components of intake (typically macronutrients) with minimal to no reduction in total caloric intake - is another alternative to CR. Many religions incorporate one or more forms of food restriction. The following religious fasting periods are featured in this review: 1) Islamic Ramadan; 2) the three principal fasting periods of Greek Orthodox Christianity (Nativity, Lent, and the Assumption); and 3) the Biblical-based Daniel Fast. This review provides a summary of the current state of knowledge related to CR and DR. A specific section is provided that illustrates related work pertaining to religious forms of food restriction. Where available, studies involving both humans and animals are presented. The review includes suggestions for future research pertaining to the topics of discussion.


TSPYL5 SNPs: association with plasma estradiol concentrations and aromatase expression.
We performed a discovery genome-wide association study to identify genetic factors associated with variation in plasma estradiol (E2) concentrations using DNA from 772 postmenopausal women with estrogen receptor (ER)-positive breast cancer prior to the initiation of aromatase inhibitor therapy. Association analyses showed that the single nucleotide polymorphisms (SNP) (rs1864729) with the lowest P value (P = 3.49E-08), mapped to chromosome 8 near TSPYL5. We also identified 17 imputed SNPs in or near TSPYL5 with P values < 5E-08, one of which, rs2583506, created a functional estrogen response element. We then used a panel of lymphoblastoid cell lines (LCLs) stably transfected with ERα with known genome-wide SNP genotypes to demonstrate that TSPYL5 expression increased after E2 exposure of cells heterozygous for variant TSPYL5 SNP genotypes, but not in those homozygous for wild-type alleles. TSPYL5 knockdown decreased, and overexpression increased aromatase (CYP19A1) expression in MCF-7 cells, LCLs, and adipocytes through the skin/adipose (I.4) promoter. Chromatin immunoprecipitation assay showed that TSPYL5 bound to the CYP19A1 I.4 promoter. A putative TSPYL5 binding motif was identified in 43 genes, and TSPYL5 appeared to function as a transcription factor for most of those genes. In summary, genome-wide significant SNPs in TSPYL5 were associated with elevated plasma E2 in postmenopausal breast cancer patients. SNP rs2583506 created a functional estrogen response element, and LCLs with variant SNP genotypes displayed increased E2-dependent TSPYL5 expression. TSPYL5 induced CYP19A1 expression and that of many other genes. These studies have revealed a novel mechanism for regulating aromatase expression and plasma E2 concentrations in postmenopausal women with ER(+) breast cancer.


Usefulness of right ventriculography compared with computed tomography for ruling out the possibility of lead perforation before lead extraction.
High-risk patients can be identified by preprocedural computed tomography (CT) before lead extraction. However, CT evaluation may be difficult especially for lead tip identification due to artifacts in the leads. Selective right ventriculography (RVG) may enable preprocedural evaluation of lead perforation. We investigated the efficacy of RVG for identifying right ventricular (RV) lead perforation compared with CT in patients who underwent lead extraction. Ninety-five consecutive patients who were examined by thin-section non-ECG-gated multidetector CT and RVG before lead extraction were investigated retrospectively. Newly recognized pericardial effusion after lead extraction was used as a reference standard for lead perforation. We analyzed the prevalence of RV lead perforation diagnosed by each method. The difference in the detection rates of lead perforation by RVG and CT was evaluated. Of the 115 RV leads in the 95 patients, lead perforation was diagnosed for 35 leads using CT, but the leads for 29 (83%) of those 35 leads diagnosed as lead perforation by CT were shown to be within the right ventricle by RVG. Three patients with 5 leads could not be evaluated by CT due to motion artifacts. The diagnostic accuracies of RVG and CT were significantly different (p < 0.001). There was no complication of pericardial effusion caused by RV lead extraction. RVG for identification of RV lead perforation leads to fewer false-positives compared to non-ECG-gated CT. However, even in cases in which lead perforation is diagnosed, most leads may be safely extracted by transvenous lead extraction.


Assessment of Knowledge about Dental Ergonomics among Dental Students of King Saud University, Riyadh, Kingdom of Saudi Arabia.
To assess the knowledge about dental ergonomics and work-related musculoskeletal disorders (WRMSDs) among dental students of King Saud University (KSU), Riyadh, Kingdom of Saudi Arabia, undergoing practical clinical training. A self-designed questionnaire after pre-testing was distributed to 150 dental students of KSU undergoing clinical training, to collect data related to (a) basic knowledge about dental ergonomics; (b) any course/workshop about dental ergonomics attended; (c) basic knowledge about WRMSDs; (d) familiarity about preventive measures to decrease the risk of WRMSDs; and (e) knowledge about treatment options for WRMSDs. One hundred forty-two students (95%) returned the completed questionnaires, of them 54 (38%) were males and 88 (62%) were females. The main findings of the study are that only 30% of the students knew about dental ergonomics; 93% of students have not attended any course/workshop about dental ergonomics; about half the students knew about WRMSDs; 62% of the students did not know about preventive measures to decrease the risk of WRMSDs, and 80% of students did not have knowledge about treatment options for WRMSDs. In general, female students had a better understanding of dental ergonomics and WRMSDs than male students. The basic knowledge of the dental ergonomics among dental students at King Saud University, Riyadh, Kingdom of Saudi Arabia is not adequate. There is a need for introducing dedicated theoretical and practical courses covering all aspects of dental ergonomics in the undergraduate curriculum of dental education.


Nonsymmetrically substituted cyclic urea HIV protease inhibitors.
A series of nonsymmetrically substituted cyclic ureacarboxamides was synthesized and evaluated for antiviral activity as a function of the inhibition of HIV-protease. Selected protease inhibitors were also evaluated for oral bioavailability. The synthesis, pharmacology, quantitative structure-activity relationship (QSAR), and pharmacokinetics for the series will be discussed.


Exosomes Mediate Epithelium-Mesenchyme Crosstalk in Organ Development.
Organ development requires complex signaling by cells in different tissues. Epithelium and mesenchyme interactions are crucial for the development of skin, hair follicles, kidney, lungs, prostate, major glands, and teeth. Despite myriad literature on cell-cell interactions and ligand-receptor binding, the roles of extracellular vesicles in epithelium-mesenchyme interactions during organogenesis are poorly understood. Here, we discovered that ∼100 nm exosomes were secreted by the epithelium and mesenchyme of a developing tooth organ and diffused through the basement membrane. Exosomes were entocytosed by epithelium or mesenchyme cells with preference by reciprocal cells rather than self-uptake. Exosomes reciprocally evoked cell differentiation and matrix synthesis: epithelium exosomes induce mesenchyme cells to produce dentin sialoprotein and undergo mineralization, whereas mesenchyme exosomes induce epithelium cells to produce basement membrane components, ameloblastin and amelogenenin. Attenuated exosomal secretion by Rab27a/b knockdown or GW4869 disrupted the basement membrane and reduced enamel and dentin production in organ culture and reduced matrix synthesis and the size of the cervical loop, which harbors epithelium stem cells, in Rab27aash/ash mutant mice. We then profiled exosomal constituents including miRNAs and peptides and further crossed all epithelium exosomal miRNAs with literature-known miRNA Wnt regulators. Epithelium exosome-derived miR135a activated Wnt/β-catenin signaling and escalated mesenchymal production of dentin matrix proteins, partially reversible by Antago-miR135a attenuation. Our results suggest that exosomes may mediate epithelium-mesenchyme crosstalk in organ development, suggesting that these vesicles and/or the molecular contents they are transporting may be interventional targets for treatment of diseases or regeneration of tissues.


Cost-effectiveness of malaria microscopy and rapid diagnostic tests versus presumptive diagnosis: implications for malaria control in Uganda.
Current Uganda National Malaria treatment guidelines recommend parasitological confirmation either by microscopy or rapid diagnostic test (RDT) before treatment with artemether-lumefantrine (AL). However, the cost-effectiveness of these strategies has not been assessed at rural operational primary care centres. Three health centres (HCs) were randomized to three diagnostic arms (microscopy, RDT and presumptive diagnosis) in a district of low and another of high malaria transmission intensities in Uganda. Some 22,052 patients presenting with fever at outpatients departments were enrolled from March 2010 to February 2011. Of these, a random sample of 1,627 was selected to measure additional socio-economic characteristics. Costing was performed following the standard step-down cost allocation and the ingredients approach. Effectiveness was measured as the number and proportion of patients correctly diagnosed and treated. Incremental Cost-Effectiveness Ratios (ICERs) were estimated from the societal perspective (http://Clinicaltrials.gov, NCT00565071). Overall RDT was most cost-effective with lowest ICER US$5.0 compared to microscopy US$9.61 per case correctly diagnosed and treated. In the high transmission setting, ICER was US$4.38 for RDT and US$12.98 for microscopy. The corresponding ICERs in the low transmission setting were US$5.85 and US$7.63 respectively. The difference in ICERs between RDT and microscopy was greater in the high transmission area (US$8.9) than in low transmission setting (US$1.78). At a willingness to pay of US$2.8, RDT remained cost effective up to a threshold value of the cost of treatment of US$4.7. RDT was cost effective in both low and high transmission settings. With a global campaign to reduce the costs of AL and RDT, the Malaria Control Programme and stakeholders need a strategy for malaria diagnosis because as the cost of AL decreases, presumptive treatment is likely to become more attractive.


Barriers and facilitators to implementing an evidence-based woman-focused intervention in South African health services.
Since the beginning of the HIV epidemic, numerous behavior change, risk-reduction, and biomedical interventions have been developed and tested. While some of these interventions have shown to be efficacious in randomized trials, it often takes almost two decades for an intervention to be translated into practice. Meanwhile, South Africa continues to have among the highest prevalence of HIV globally, with women of childbearing age bearing the burden of the epidemic. Given the urgency of the HIV epidemic among vulnerable women in South Africa, it is imperative that evidence-based interventions be implemented rapidly into practice. This study presents a first step toward examining the acceptability and feasibility of implementing the Women's Health CoOp (WHC) in clinics and substance abuse rehab settings in Cape Town, South Africa. We conducted focus group discussions with women who use substances and with service providers, we also conducted in-depth interviews with health service planners. Our goal was to examine implementation and clinical outcomes associated with delivery of the WHC across clinics and substance abuse rehab programs. All participants agreed on the need for the WHC. Perceived facilitators to implementing the WHC included the recognizable need for programs to empower women and to build the capacity of staff to address issues of substance use, sexual risk, and intimate partner violence. Participants also identified potential barriers to women engaging with this program, including the stigma women experience when seeking services and the lack of person-centered care at healthcare facilities. In a country with the largest number of women of childbearing age living with HIV, an evidence-based woman-focused intervention that comprehensively addresses women's risk for suboptimal antiretroviral adherence may be essential for reducing HIV incidence. However, potential barriers to implementing the WHC successfully must be addressed before the program can be fully integrated into the services delivered by healthcare facilities. Clinical trials NCT02733003 . Date of Registration: January 21, 2016, registered retroactively after participant enrollment.


Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes.
Parkinson´s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Aggravation of symptoms is mirrored by accumulation of protein aggregates mainly composed by alpha-synuclein in different brain regions, called Lewy bodies (LB). Previous studies have identified several molecular mechanisms as autophagy and inflammation playing a role in PD pathogenesis. Increased insights into mechanisms involved in early disease stages and driving the progression of the LB pathology are required for the development of disease-modifying strategies. Here, we aimed to elucidate disease stage-specific transcriptomic changes in brain tissue of well-characterized PD and control donors. We collected frontal cortex samples from 84 donors and sequenced both the coding and non-coding RNAs. We categorized our samples into groups based on their degree of LB pathology aiming to recapitulate a central aspect of disease progression. Using an analytical pipeline that corrected for sex, age at death, RNA quality, cell composition and unknown sources of variation, we found major disease stage-specific transcriptomic changes. Gene expression changes were most pronounced in donors at the disease stage when microscopic LB changes first occur in the sampled brain region. Additionally, we identified disease stage-specific enrichment of brain specific pathways and immune mechanisms. On the contrary, we showed that mitochondrial mechanisms are enriched throughout the disease course. Our data-driven approach also suggests a role for several poorly characterized lncRNAs in disease development and progression of PD. Finally, by combining genetic and epigenetic information, we highlighted two genes (MAP4K4 and PHYHIP) as candidate genes for future functional studies. Together our results indicate that transcriptomic dysregulation and associated functional changes are highly disease stage-specific, which has major implications for the study of neurodegenerative disorders.


Burden of severe rotavirus diarrhea in indonesia.
Globally, rotavirus is the leading cause of diarrhea-related hospitalizations and deaths among young children, but the burden of rotavirus disease in Indonesia is poorly documented. From January through December 2006, we conducted prospective surveillance (inpatient and outpatient) among children aged <5 years at 6 hospitals in 6 provinces of Indonesia, using standardized methodology. Of 2240 enrolled children hospitalized for diarrhea, 1345 (60%) were rotavirus positive. Of 176 children enrolled in outpatient clinics in 3 hospitals, 73 (41%) were rotavirus positive. Among children hospitalized for diarrhea, dehydration was more common among those who tested positive for rotavirus than among those who did not (91% vs 82%; P < .05), as was vomiting (86% vs 67%; P < .05). Children aged 6-23 months experienced 72% of all rotavirus episodes. Rotavirus prevalence increased slightly in the cool, dry season. The most commonly detected genotypes were G9 (30%) and P[6] (56%). G1P[6] and G9P[6] accounted for 34% and 21% of strains, respectively. A high proportion of genotype P[6] was detected, in combination with the common G types G1 and G9. Available rotavirus vaccines would likely be efficacious against the most common circulating strains, but continued monitoring of uncommon genotypes is needed.


Protective effects of melatonin and omega-3 on the hippocampus and the cerebellum of adult Wistar albino rats exposed to electromagnetic fields.
The purpose of the study was to investigate the effects of pulsed digital electromagnetic radiation emitted by mobile phones on the central nervous system of the adult Wistar albino rats. The study evaluated structural and functional impacts of four treatment arms: electromagnetic field (EMF) exposed; EMF exposed + melatonin treated group (EMF + Mel); EMF exposed + omega-3 (ω3) treated group (EMF + ω3); and control group (Cont). The 12-weeks-old rats were exposed to 900 MHz EMF for 60 min/day (4:00-5:00 p.m.) for 15 days. Stereological, biochemical and electrophysiological techniques were applied to evaluate protective effects of Mel and ω3. Significant cell loss in the CA1 and CA2 regions of hippocampus were observed in the EMF compared to other groups (p < 0.01). In the CA3 region of the EMF + ω3, a significant cell increase was found compared to other groups (p < 0.01). Granular cell loss was observed in the dentate gyrus of the EMF compared to the Cont (p < 0.01). EMF + ω3 has more granular cells in the cerebellum than the Cont, EMF + Mel (p < 0.01). Significant Purkinje cell loss was found in the cerebellum of EMF group compared to the other (p < 0.01). EMF + Mel and EMF + ω3 showed the same protection compared to the Cont (p > 0.05). The passive avoidance test showed that entrance latency into the dark compartment was significantly shorter in the EMF (p < 0.05). Additionally, EMF had a higher serum enzyme activity than the other groups (p < 0.01). In conclusion, our analyses confirm that EMF may lead to cellular damage in the hippocampus and the cerebellum, and that Mel and ω3 may have neuroprotective effects.


Rec8p, a meiotic recombination and sister chromatid cohesion phosphoprotein of the Rad21p family conserved from fission yeast to humans.
Our work and that of others defined mitosis-specific (Rad21 subfamily) and meiosis-specific (Rec8 subfamily) proteins involved in sister chromatid cohesion in several eukaryotes, including humans. Mutation of the fission yeast Schizosaccharomyces pombe rec8 gene was previously shown to confer a number of meiotic phenotypes, including strong reduction of recombination frequencies in the central region of chromosome III, absence of linear element polymerization, reduced pairing of homologous chromosomes, reduced sister chromatid cohesion, aberrant chromosome segregation, defects in spore formation, and reduced spore viability. Here we extend the description of recombination reduction to the central regions of chromosomes I and II. We show at the protein level that expression of rec8 is meiosis specific and that Rec8p localizes to approximately 100 foci per prophase nucleus. Rec8p was present in an unphosphorylated form early in meiotic prophase but was phosphorylated prior to meiosis I, as demonstrated by analysis of the mei4 mutant blocked before meiosis I. Evidence for the persistence of Rec8p beyond meiosis I was obtained by analysis of the mutant mes1 blocked before meiosis II. A human gene, which we designate hrec8, showed significant primary sequence similarity to rec8 and was mapped to chromosome 14. High mRNA expression of mouse and human rec8 genes was found only in germ line cells, specifically in testes and, interestingly, in spermatids. hrec8 was also expressed at a low level in the thymus. Sequence similarity and testis-specific expression indicate evolutionarily conserved functions of Rec8p in meiosis. Possible roles of Rec8p in the integration of different meiotic events are discussed.


Quality of life and satisfaction with outcome among prostate-cancer survivors.
We sought to identify determinants of health-related quality of life after primary treatment of prostate cancer and to measure the effects of such determinants on satisfaction with the outcome of treatment in patients and their spouses or partners. We prospectively measured outcomes reported by 1201 patients and 625 spouses or partners at multiple centers before and after radical prostatectomy, brachytherapy, or external-beam radiotherapy. We evaluated factors that were associated with changes in quality of life within study groups and determined the effects on satisfaction with the treatment outcome. Adjuvant hormone therapy was associated with worse outcomes across multiple quality-of-life domains among patients receiving brachytherapy or radiotherapy. Patients in the brachytherapy group reported having long-lasting urinary irritation, bowel and sexual symptoms, and transient problems with vitality or hormonal function. Adverse effects of prostatectomy on sexual function were mitigated by nerve-sparing procedures. After prostatectomy, urinary incontinence was observed, but urinary irritation and obstruction improved, particularly in patients with large prostates. No treatment-related deaths occurred; serious adverse events were rare. Treatment-related symptoms were exacerbated by obesity, a large prostate size, a high prostate-specific antigen score, and older age. Black patients reported lower satisfaction with the degree of overall treatment outcomes. Changes in quality of life were significantly associated with the degree of outcome satisfaction among patients and their spouses or partners. Each prostate-cancer treatment was associated with a distinct pattern of change in quality-of-life domains related to urinary, sexual, bowel, and hormonal function. These changes influenced satisfaction with treatment outcomes among patients and their spouses or partners.


#MeToo in EM: A Multicenter Survey of Academic Emergency Medicine Faculty on Their Experiences with Gender Discrimination and Sexual Harassment.
Gender-based discrimination and sexual harassment of female physicians are well documented. The #MeToo movement has brought renewed attention to these problems. This study examined academic emergency physicians' experiences with workplace gender discrimination and sexual harassment. We conducted a cross-sectional survey of a convenience sample of emergency medicine (EM) faculty across six programs. Survey items included the following: the Overt Gender Discrimination at Work (OGDW) Scale; the frequency and source of experienced and observed discrimination; and whether subjects had encountered unwanted sexual behaviors by a work superior or colleague in their careers. For the latter question, we asked subjects to characterize the behaviors and whether those experiences had a negative effect on their self-confidence and career advancement. We made group comparisons using t-tests or chi-square analyses, and evaluated relationships between gender and physicians' experiences using correlation analyses. A total of 141 out of 352 (40.1%) subjects completed at least a portion of the survey. Women reported higher mean OGDW scores than men (15.4 vs 10.2; 95% confidence interval [CI], 3.6-6.8). Female faculty were also more likely to report having experienced gender-based discriminatory treatment than male faculty (62.7% vs 12.5%; 95% CI, 35.1%-65.4%), although male and female faculty were equally likely to report having observed gender-based discriminatory treatment of another physician (64.7% vs 56.3%; 95% CI, 8.6%-25.5%). The three most frequent sources of experienced or observed gender-based discriminatory treatment were patients, consulting or admitting physicians, and nursing staff. The majority of women reported having encountered unwanted sexual behaviors in their careers, with a significantly greater proportion of women reporting them compared to men (52.9% vs 26.2%, 95% CI, 9.9%-43.4%). The majority of unwanted behaviors were sexist remarks and sexual advances. Of those respondents who encountered these unwanted behaviors, 22.9% and 12.5% reported at least somewhat negative effects on their self-confidence and career advancement. Female EM faculty perceived more gender-based discrimination in their workplaces than their male counterparts. The majority of female and approximately a quarter of male EM faculty encountered unwanted sexual behaviors in their careers.


The Smc5-Smc6 complex regulates recombination at centromeric regions and affects kinetochore protein sumoylation during normal growth.
The Smc5-Smc6 complex in Saccharomyces cerevisiae is both essential for growth and important for coping with genotoxic stress. While it facilitates damage tolerance throughout the genome under genotoxin treatment, its function during unperturbed growth is mainly documented for repetitive DNA sequence maintenance. Here we provide physical and genetic evidence showing that the Smc5-Smc6 complex regulates recombination at non-repetitive loci such as centromeres in the absence of DNA damaging agents. Mutating Smc6 results in the accumulation of recombination intermediates at centromeres and other unique sequences as assayed by 2D gel analysis. In addition, smc6 mutant cells exhibit increased levels of Rad52 foci that co-localize with centromere markers. A rad52 mutation that decreases centromeric, but not overall, levels of Rad52 foci in smc6 mutants suppresses the nocodazole sensitivity of these cells, suggesting that the Smc6-mediated regulation of recombination at centromeric regions impacts centromere-related functions. In addition to influencing recombination, the SUMO ligase subunit of the Smc5-Smc6 complex promotes the sumoylation of two kinetochore proteins and affects mitotic spindles. These results suggest that the Smc5-Smc6 complex regulates both recombination and kinetochore sumoylation to facilitate chromosomal maintenance during growth.


The relationship between financial incentives and quality of diabetes care in Ontario, Canada.
We assessed the impact of a diabetes incentive code introduced for primary care physicians in Ontario, Canada, in 2002 on quality of diabetes care at the population and patient level. We analyzed administrative data for 757,928 Ontarians with diabetes to examine the use of the code and receipt of three evidence-based monitoring tests from 2006 to 2008. We assessed testing rates over time and before and after billing of the incentive code. One-quarter of Ontarians with diabetes had an incentive code billed by their physician. The proportion receiving the optimal number of all three monitoring tests (HbA(1c), cholesterol, and eye tests) rose gradually from 16% in 2000 to 27% in 2008. Individuals who were younger, lived in rural areas, were not enrolled in a primary care model, or had a mental illness were less likely to receive all three recommended tests. Patients with higher numbers of incentive code billings in 2006-2008 were more likely to receive recommended testing but also were more likely to have received the highest level of recommended testing prior to introduction of the incentive code. Following the same patients over time, improvement in recommended testing was no greater after billing of the first incentive code than before. The diabetes incentive code led to minimal improvement in quality of diabetes care at the population and patient level. Our findings suggest that physicians who provide the highest quality care prior to incentives may be those most likely to claim incentive payments.


Gerstmann'S syndrome in acute stroke patients.
Gerstmann in 1924. observed in a few patients a concomitant impairment in discriminating their own fingers, writing by hand, distinguishing left from right and performing calculations. He claimed that this tetrad of symptoms constituted a syndromal entity, assigned it to a lesion of the dominant parietal lobe. Since than, Gerstmann`s syndrome (GS) was enigma for neuropsychologists. The aim of this study was to analyze frequency and clinical features of GS among acute stroke patients. We prospectively analyzed 194 acute stroke patients (average age 65±11.06 years, male 113 (58.2%), female 81 (41.8%) hospitalized at department of Neurology, University Clinical Center tuzla, during the six mounths in 2010. For clinical assessment of agraphia, alexia and acalculia we used Minessota test for differential diagnosis of aphasia's. Among these acute stroke patients, 59 (30.40%) had alexia, agraphia and acalculia or different combinations of these disorders. two patients (3.4%) had agraphia and acalculia associated with other part of tetrad of GS: fi nger agnosia and left-right disorientation. they both where men, right handed, and cranial computed tomography scan showed ischemic lesion in the left parietal and left temporoparietal lobe. Gerstmann`s syndrome is rare clinical entity, and has the high value in localization and the lesion is mainly localized to angular gyrus of the dominant hemisphere.


Evidence of cave use by savanna chimpanzees (Pan troglodytes verus) at Fongoli, Senegal: implications for thermoregulatory behavior.
Much attention has been paid to how humans both adapt and acclimate to heat stress, primarily due to the relevance of these issues to hominid evolution in open Plio-Pleistocene environments. However, little is known about the responses of human's closest living relative, the chimpanzee (Pan troglodytes), to similar environmental stressors. In southeastern Senegal, one of the hottest and driest habitats that chimpanzees (P. t. verus) live in today, apes rely on behavioral mechanisms of dealing with thermal stress. Chimpanzees' use of caves was based primarily on indirect evidence (feeding traces, feces, and hairs) gathered from one cave from January to December 2004, but data from observational records collected from May 2001 through March 2006 supplement these data. The hypothesis that chimpanzees' use of caves is a response to heat was tested by collecting data on temperatures within the largest cave and in different habitats used by chimpanzees, such as gallery forest and woodland. Results indicate that chimpanzees primarily use caves as shelters during the hottest times of year and that caves are consistently and significantly cooler than open habitats. Insight into the way that chimpanzees in Senegal cope with extreme temperatures may help us to better understand the behavior of early hominids in such an environment.


Evaluation of the field relevance of several injury risk functions.
An evaluation of the four injury risk curves proposed in the NHTSA NCAP for estimating the risk of AIS>= 3 injuries to the head, neck, chest and AIS>=2 injury to the Knee-Thigh-Hip (KTH) complex has been conducted. The predicted injury risk to the four body regions based on driver dummy responses in over 300 frontal NCAP tests were compared against those to drivers involved in real-world crashes of similar severity as represented in the NASS. The results of the study show that the predicted injury risks to the head and chest were slightly below those in NASS, and the predicted risk for the knee-thigh-hip complex was substantially below that observed in the NASS. The predicted risk for the neck by the Nij curve was greater than the observed risk in NASS by an order of magnitude due to the Nij risk curve predicting a non-zero risk when Nij = 0. An alternative and published Nte risk curve produced a risk estimate consistent with the NASS estimate of neck injury. Similarly, an alternative and published chest injury risk curve produced a risk estimate that was within the bounds of the NASS estimates. No published risk curve for femur compressive load could be found that would give risk estimates consistent with the range of the NASS estimates. Additional work on developing a femur compressive load risk curve is recommended.


Interactions of coffee consumption and postmenopausal hormone use in relation to breast cancer risk in UK Biobank.
We investigated the association of coffee consumption with postmenopausal breast cancer risk, overall and by the status of postmenopausal hormone therapy (PMH). This study included 126,182 postmenopausal women (2,636 with breast cancer and 123,546 without) from UK Biobank. Cancer diagnoses were ascertained through the linkage to the UK National Health Service Central Registers. Information on breast cancer risk factors and coffee consumption was collected at baseline and updated during follow-up. We used Cox proportional hazards regression to evaluate associations between coffee consumption and breast cancer, overall and in stratified analyses by woman's PMH status (none, past, current). In the overall analysis, coffee consumption was not associated with breast cancer risk (Hazard Ratio [HR] 1.00, 95% CI 0.91-1.11 for 2-3 cups/day, and HR 0.98, 95% CI 0.87-1.10 for ≥ 4 cups/day, p-trend = 0.69). Women with no PMH history who consumed ≥ 4 cups/day had a 16% reduced risk of breast cancer as compared to women who consumed < 7 cups/week (HR 0.84, 95% CI 0.71-1.00). Among women with past PMH, those consuming ≥ 4 cups/day had a 22% greater risk of breast cancer than women consuming < 7 cups/week (HR 1.22, 95% CI 1.01-1.47). No association was found among current PMH users. We found no significant interaction between PMH and coffee consumption (p = 0.24). Coffee consumption might be associated with increased breast cancer risk in women who used hormones in the past. Further studies are warranted to confirm these findings and elucidate potential biological mechanisms underlying the observed associations.


Is 50 cent the price of the optimal copayment? - a qualitative study of patient opinions and attitudes in response to a 50 cent charge on prescription drugs in a publicly funded health system in Ireland.
A 50 cent prescription levy was introduced in 2010 on the General Medical Services (GMS) scheme (Irish public health insurance). This study sought to examine patient attitudes and opinions surrounding the 50 cent copayment. Given the small momentary value of the prescription fee, these results are of interest to policymakers internationally who wish to reduce copayments rather than abolish them. A qualitative research design was used; semi structured interviews were carried out. Twenty four GMS eligible participants were interviewed in 23 interviews. Fifteen females and 9 males took part. Ages varied from 31- >70 years. Patients were invited to be interviewed in both independent and chain community pharmacies in three types of setting; 1) a socially deprived urban area, 2) a suburban affluent area and 3) a rural area. The Framework method was used for data management and analysis using QSR International's NVivo 9.2 qualitative data analysis software. The "Francis method" was used to test for data saturation. Results are of interest to the Irish context and also at a broader international level. Patients were mostly accepting of the prescription levy with some reservations concerning an increased price and the way in which generated revenue would be used by government. Participants identified waste of prescription drugs at the hand of patients (moral hazard), but there was discordant opinion on whether the 50 cent copayment would halt this moral hazard. Interviewees felt the levy was affordable, albeit some may suffer a financial impact more than others. This qualitative study gives important insights into the experiences of GMS patients with regard to the prescription levy. Information regarding the appropriateness of a 50 cent copayment as a symbolic copayment needs to be confirmed by quantitative analysis. Further insight is required from a younger population.


Measures of childhood fitness and body mass index are associated with bone mass in adulthood: a 20-year prospective study.
The long-term effects of childhood exercise and body mass index (BMI) on bone mass remain uncertain. We measured 1434 children, 7-15 yr of age, as part of the Australian Schools Health and Fitness Survey in 1985 and approximately 20 yr later (mean age, 31 yr). Fitness measures included a 1.6-km run and a 50-m sprint (childhood only), leg strength, standing long jump, and physical work capacity at 170 beats/min (PWC(170); childhood and adulthood). BMI was assessed at both time points. A single Sahara bone ultrasound densitometer was used to determine heel bone mass. We found, in females, there were modest but significant beneficial relationships between the childhood 1.6-km run, 50-m sprint, standing long jump, and adult bone mass. In both sexes, PWC(170) at 9 yr of age had a greater influence on adult bone mass (r(2) = 5-8%, all p < 0.05) than it did for 15 yr olds (r(2) = <1%, all p > 0.05), independent of adult performance. In the 12 yr olds, childhood PWC(170) was also associated with female adult bone mass (broadband ultrasound attenuation: r(2) = 6%, p = 0.045). In males, childhood BMI (but no performance measures) was positively associated with adult bone mass after adjustment for adult BMI. In conclusion, childhood fitness levels, particularly in females and in the early pubertal years, are predictive of adult skeletal status as measured by quantitative ultrasound, whereas BMI is predictive in males only. These results suggest that increased skeletal loading in childhood leads to an increase in peak bone mass independent of current loading.


Alzheimer's disease and Helicobacter pylori infection: Defective immune regulation and apoptosis as proposed common links.
Although degenerative diseases of the central nervous system, including Alzheimer's disease (AD), have an increasingly high impact on aged population their association with Helicobacter pylori (H. pylori) infection has not as yet been thoroughly researched. Current H. pylori infection appears to induce irregular humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of nerves, thereby contributing and possibly perpetuating the apoptotic neural tissue damage observed in neurodegenerative diseases including AD. An association between AD and H. pylori infection has been recently addressed by two studies. A higher seropositivity for anti-H. pylori immunoglobulin G antibodies in 30 patients with AD than in 30 age-matched controls was reported in one study; this serological test, however, has limitations because it does not discriminate between current and old infections. In the other study, by introducing the histological method (the actual gold standard) for diagnosis of H. pylori infection, we reported a higher prevalence of H. pylori infection in 50 AD patients than in 30 anemic controls. This pathogen may influence the pathophysiology of AD by promoting platelet and platelet-leukocyte aggregation; releasing various pro-inflammatory and vasoactive substances; developing cross-mimicry with host antigens; producing reactive oxygen metabolites and circulating lipid peroxides; influencing the apoptotic process; and increasing, through induction of atrophic gastritis, homocysteine, which contributes to vascular disorders implicated in endothelial damage and neurodegeneration.


Salivary phosphate-binding chewing gum reduces hyperphosphatemia in dialysis patients.
In uremic patients, hyperphosphatemia is associated with cardiovascular calcification and increased cardiovascular mortality. Despite the use of phosphate binders, only half of hemodialysis (HD) patients achieve recommended serum phosphate levels. A hyperphosphoric salivary content, which correlates linearly with serum phosphate, has been reported in HD patients. We hypothesized that binding salivary phosphate during periods of fasting in addition to using phosphate binders with meals could improve the treatment of hyperphosphatemia. We assessed the phosphate-binding capacity of the natural polymer chitosan by (31)P nuclear magnetic resonance and established that 10 and 20% (wt/vol) middle viscosity chitosan solutions bind 30 and 50% of the phosphate contained in PBS, respectively. Thirteen HD patients with serum phosphate levels >6.0 mg/dl despite treatment with sevelamer hydrochloride chewed 20 mg of chitosan-loaded chewing gum twice daily for 2 wk at fast in addition to their prescribed phosphate-binding regimen. Salivary phosphate and serum phosphate significantly decreased during the first week of chewing; by the end of 2 wk, salivary phosphate decreased 55% from baseline (73.21 +/- 19.19 to 33.19 +/- 6.53; P < 0.00001), and serum phosphate decreased 31% from baseline (7.60 +/- 0.91 to 5.25 +/- 0.89 mg/dl; P < 0.00001). Salivary phosphate returned to baseline by day 15 after discontinuing the chewing gum, whereas serum phosphate levels took 30 d to return to baseline. Parathyroid hormone and serum calcium concentrations were not affected by the gum. In conclusion, adding salivary phosphate binding to traditional phosphate binders could be a useful approach for improving treatment of hyperphosphatemia in HD patients.


Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin.
Mice rendered deficient in lymphotoxin (LT) by gene targeting in embryonic stem cells have no morphologically detectable lymph nodes or Peyer's patches, although development of the thymus appears normal. Within the white pulp of the spleen, there is failure of normal segregation of B and T cells. Spleen and peripheral blood contain CD4+CD8- and CD4-CD8+ T cells in a normal ratio, and both T cells subsets have an apparently normal lytic function. Lymphocytes positive for immunoglobulin M are present in increased numbers in both the spleen and peripheral blood. These data suggest an essential role for LT in the normal development of peripheral lymphoid organs.


Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers.
To investigate the outcome of cardiac evaluation and the risk stratification for sudden cardiac death (SCD) in asymptomatic hypertrophic cardiomyopathy (HCM) mutation carriers. Seventy-six HCM mutation carriers from 32 families identified by predictive DNA testing underwent cardiac evaluation including history, examination, electrocardiography, Doppler echocardiography, exercise testing, and 24 h Holter monitoring. The published diagnostic criteria for HCM in adult members of affected families were used to diagnose HCM. Thirty-three (43%) men and 43 (57%) women with a mean age of 42 years (range 16-79) were examined; in 31 (41%) HCM was diagnosed. Disease penetrance was age related and men were more often affected than women (P = 0.04). Myosin Binding Protein C (MYBPC3) mutation carriers were affected at higher age than Myosin Heavy Chain (MYH7) mutation carriers (P = 0.01). Risk factors for SCD were present in affected and unaffected carriers. Hypertrophic cardiomyopathy was diagnosed in 41% of carriers. Disease penetrance was age dependent, warranting repeated cardiologic evaluation. The MYBPC3 mutation carriers were affected at higher age than MYH7 mutation carriers. Risk factors for SCD were present in carriers with and without HCM. Follow-up studies are necessary to evaluate the effectiveness of risk stratification for SCD in this population.


Pre-clinical evaluation of a next-generation spray adhesion barrier for multiple site adhesion protection.
Intra-abdominal adhesions represent a major cause of postoperative morbidity, including chronic or recurrent pelvic pain and infertility in a significant percent of patients. The SprayShield™ Adhesion Barrier System (Covidien, Waltham, MA) is a next-generation sprayable adhesion barrier to prevent postoperative adhesions. Initially sprayed as a liquid, SprayShield™ solidifies within 2 seconds of contact with tissue through a polyethylene glycol (PEG) ester-Trilysine reaction to form an adherent, internal tissue barrier that protects the underlying tissues for several days after surgery. After tissue begins to heal, the adhesion barrier liquefies via hydrolysis and completely absorbs within 7 days. Safety testing has shown the product to be nongenotoxic, noncytotoxic, nonsensitizing, and nonirritating. SprayShield™ has been shown to adhere well to tissue, with the mechanism of adherence believed to be mainly due to tissue surface mechanical interlocking. In studies that compared SprayShield™ to good surgical technique, virgin hogs were randomized to receive SprayShield™ or good surgical technique (Control). Compared to Controls, SprayShield™ demonstrated a statistically significant reduction in the number of adhesions (46%, p=0.04) and in the area of adhesions (83%, p=0.012) to injured sites. With its ease of application, biocompatibility and adhesion prevention efficacy, SprayShield™ may be an effective next-generation adhesion prevention product for open and laparoscopic abdominopelvic procedures as an adjunct to good surgical technique.


Manipulation of electron orbitals in hard-wall InAs/InP nanowire quantum dots.
We present a novel technique for the manipulation of the energy spectrum of hard-wall InAs/InP nanowire quantum dots. By using two local gate electrodes, we induce a strong transverse electric field in the dot and demonstrate the controlled modification of its electronic orbitals. Our approach allows us to dramatically enhance the single-particle energy spacing between the first two quantum levels in the dot and thus to increment the working temperature of our InAs/InP single-electron transistors. Our devices display a very robust modulation of the conductance even at liquid nitrogen temperature, while allowing an ultimate control of the electron filling down to the last free carrier. Potential further applications of the technique to time-resolved spin manipulation are also discussed.


Smokers report greater demand for alcohol on a behavioral economic purchase task.
Cigarette smokers have higher levels of alcohol consumption than nonsmokers and poorer response to alcohol treatment. It is possible that the greater severity of alcohol problems observed in smokers reflects a greater susceptibility to alcohol-related reinforcement. The present study used a behavioral economic purchase task to investigate whether heavy drinking smokers would have greater demand for alcohol than heavy drinking nonsmokers. Participants were 207 college students who reported at least one heavy drinking episode in the past month. Of the 207 participants, 33.2% (n = 67) reported smoking cigarettes at least 1 day in the past month. Participants completed the hypothetical alcohol purchase task, a simulation task that asked them to report how many drinks they would purchase at varying price increments. After the participants' reported alcohol consumption, gender, alcohol problems, and depression were controlled for, analyses of covariance revealed that heavy drinking smokers had significantly greater reported maximum alcohol expenditures (Omax), greater maximum inelastic price (Pmax), and higher breakpoint values (first price suppressing consumption to zero). College student heavy drinkers who also smoke cigarettes exhibit increased demand for alcohol. Smokers in this high-risk developmental stage may thus be less sensitive to price and other contingencies that would otherwise serve to modulate drinking and may require more intensive intervention approaches.


Changing the site energy of per-614 in the Peridinin-chlorophyll a-protein does not alter its capability of chlorophyll triplet quenching.
The peridinin-chlorophyll-a protein (PCP) is a water-soluble light harvesting protein of the dinoflagellate Amphidinium carterae, employing peridinin (Per) as the main carotenoid to fulfil light harvesting and photo-protective functions. Per molecules bound to the protein experience specific molecular surroundings which lead to different electronic and spectral properties. In the refolded N89 L variant PCP (N89 L-RFPCP) a significant part of the intensity on the long wavelength side of the absorption spectrum is shifted to shorter wavelengths due to a significant change in the Per-614 site energy. Since Per-614 has been shown to be the main chlorophyll (Chl) triplet quencher in the protein, and the relative geometry of pigments is not affected by the mutation as verified by X-ray crystallography, this variant is ideally suited to study the dependence of the triplet-triplet energy transfer (TTET) mechanism on the pigment site energy. By using a combination of Optically Detected Magnetic Resonance (ODMR), pulse Electron Paramagnetic Resonance (EPR) and Electron Nuclear DOuble Resonance (ENDOR) we found that PCP maintains the efficient Per-614-to-Chl-a TTET despite the change of Per-614 local energy. This shows the robustness of the photoprotective site, which is very important for the protection of the system.


Optimising decentralisation for the health sector by exploring the synergy of decision space, capacity and accountability: insights from the Philippines.
Several studies on decentralisation have used the 'decision space' approach to assess the breadth of space made available to decision-makers at lower levels of the health system. However, in order to better understand how decentralisation becomes effective for the health sector, analysis should go beyond assessing decision space and include the dimensions of capacity and accountability. Building on Bossert's earlier work on the synergy of these dimensions, we analysed decision-making in the Philippines where governmental health services have been devolved to local governments since 1992. Using a qualitative research design, we interviewed 27 key decision-makers at different levels of the Philippine health system and representing various local settings. We explored their perspectives on decision space, capacities and accountability in the health sector functions of planning, financing and budget allocation, programme implementation and service delivery, management of facilities, equipment and supplies, health workforce management, and data monitoring and utilisation. Analysis followed the Framework Method. Across all functions, decision space for local decision-makers was assessed to be moderate or narrow despite 25 years of devolution. To improve decision-making in these functions, adjustments in local capacities should include, at the individual level, skills for strategic planning, management, priority-setting, evidence-informed policy-making and innovation in service delivery. At institutional levels, these desired capacities should include having a multi-stakeholder approach, generating revenues from local sources, partnering with the private sector and facilitating cooperation between local health facilities. On the other hand, adjustments in accountability should focus on the various mechanisms that can be enforced by the central level, not only to build the desired capacities and augment the inadequacies at local levels, but also to incentivise success and regulate failure by the local governments in performing the functions transferred to them. To optimise decentralisation for the health sector, widening decision spaces for local decision-makers must be accompanied by the corresponding adjustments in capacities and accountability for promoting good decision-making at lower levels in the decentralised functions. Analysing the health system through the lens of this synergy is useful for exploring concrete policy adjustments in the Philippines as well as in other settings.


Integrated Cancer Subtyping using Heterogeneous Genome-Scale Molecular Datasets.
Vast repositories of heterogeneous data from existing sources present unique opportunities. Taken individually, each of the datasets offers solutions to important domain and source-specific questions. Collectively, they represent complementary views of related data entities with an aggregate information value often well exceeding the sum of its parts. Integration of heterogeneous data is therefore paramount to i) obtain a more unified picture and comprehensive view of the relations, ii) achieve more robust results, iii) improve the accuracy and integrity, and iv) illuminate the complex interactions among data features. In this paper, we have proposed a data integration methodology to identify subtypes of cancer using multiple data types (mRNA, methylation, microRNA and somatic variants) and different data scales that come from different platforms (microarray, sequencing, etc.). The Cancer Genome Atlas (TCGA) dataset is used to build the data integration and cancer subtyping framework. The proposed data integration and disease subtyping approach accurately identifies novel subgroups of patients with significantly different survival profiles. With current availability of vast genomics, and variant data for cancer, the proposed data integration system will better differentiate cancer and patient subtypes for risk and outcome prediction and targeted treatment planning without additional cost and precious lost time.


Antimicrobial and antioxidant activities of the extracts and compounds from the leaves of Psorospermum aurantiacum Engl. and Hypericum lanceolatum Lam.
Psorospermun aurantiacum and Hypericum lanceolatum are plants locally used in Cameroon and other parts of Africa for the treatment of gastrointestinal and urinary tract infections, skin infections, venereal diseases, gastrointestinal disorder, infertility, epilepsy as well as microbial infections. The present study was designed in order to investigate the in vitro antimicrobial and radical scavenging activities of the extracts and isolated compounds from the leaves of these plants. The plant extract was prepared by maceration in ethyl acetate and methanol and fractionated by column chromatography. The structures of isolated compounds were elucidated by spectroscopic analyses in conjunction with literature data. The broth microdilution method was used to evaluate the in vitro antimicrobial activity against bacteria, yeasts and dermatophytes. The antioxidant potentials of the extracts and their isolated compounds were evaluated using the DPPH radical scavenging method. Five known compounds: physcion (1), 1,8-dihydroxy-3-geranyloxy-6-methylanthraquinone (2), kenganthranol B (3), vismiaquinone (4), and octacosanol (5) were isolated from the leaves of P. aurantiacum while six compounds including friedelin (6), betulinic acid (7), 2,2',5,6'-tetrahydroxybenzophenone (8), allanxanthone A (9), 1,3,6- trihydroxyxanthone (10) and isogarcinol (11) were isolated from H. lanceolatum. Compound 8 and 4 exhibited the highest antibacterial and antifungal activities with MIC ranges of 2-8 μg/ml and 4-32 μg/ml respectively. P. aurantiacum crude extract (Rsa50 = 6.359 ± 0.101) showed greater radical scavenging activity compared with H. lanceolatum extract (Rsa50 = 30.996 ± 0.879). Compound 11 showed the highest radical scavenging activity (RSa50 = 1.012 ± 0.247) among the isolated compounds, comparable to that of L-arscobic acid (RSa50 = 0.0809 ± 0.045). The experimental findings show that the ethyl acetate and methanol extracts and isolated compounds from P. aurantiacum and H. lanceolatum stem bark possess significant antimicrobial and antioxidant activities justifying the use of these plants in traditional medicine, which may be developed as phytomedicines.


Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu.
To clarify the role of the Shc-Grb2-Sos trimer in the oncogenic signaling of the point mutation-activated HER-2/neu receptor tyrosine kinase (named p185), we interfered with the protein-protein interactions in the Shc.Grb2.Sos complex by introducing Grb2 mutants with deletions in either amino- (delta N-Grb2) or carboxyl-(delta C-Grb2) terminal SH3 domains into B104-1-1 cells derived from NIH3T3 cells expressing the point mutation-activated HER-2/neu. We found that the transformed phenotypes of the B104-1-1 cells were largely reversed by the delta N-Grb2. The effect of the delta C-Grb2 was much weaker. Biochemical analysis showed that the delta N-Grb2 was able to associate Shc but not p185 or Sos, while the delta C-Grb2 bound to Shc, p185, and Sos. The p185-mediated Ras activation was severely inhibited by the delta N-Grb2 but not the delta C-Grb2. Taken together, these data demonstrate that interruption of the interaction between Shc and the endogenous Grb2 by the delta N-Grb2 impairs the oncogenic signaling of the activated p185, indicating that (i) the delta N-Grb2 functions as a strong dominant-negative mutant, and (ii) Shc/Grb2/Sos pathway plays a major role in mediating the oncogenic signal of the activated p185. Unlike the delta N-Grb2, delta C-Grb2 appears to be a relatively weak dominant-negative mutant, probably due to its ability to largely fulfill the biological functions of the wild-type Grb2.


Copy number variations in 6q14.1 and 5q13.2 are associated with alcohol dependence.
Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence and all common copy number variations (CNVs) with good reliability in the Study of Addiction: Genetics and Environment (SAGE). All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism, as a part of 3 contributing studies. A total of 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVPartition, PennCNV, and QuantiSNP, and only CNVs identified by all 3 software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory. CNVs in 6q14.1 (p = 1.04 × 10(-6)) and 5q13.2 (p = 3.37 × 10(-4)) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2, there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation and language delay. The CNV in 5q13.2 was validated, whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution. This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence.


Methodological issues for a large-scale intervention trial of lifestyle modification: Interim assessment of the high-risk and population strategy for occupational health promotion (HIPOP-OHP) study.
To clarify the methodological issues for the High-risk and population Strategy for Occupational Health Promotion Study (HIPOP-OHP study), which is a 4-year non-randomized control trial, an interim assessment of male participants was performed 3 years after the baseline survey. We had approximately 2,500 and 4,000 participants in the intervention and control groups, respectively. The population measures and prevalence of risk factors at each year, and between the baseline and 4th examinations were compared between the two groups. The personal trends of returning participants who were in the study at the 1(st) and 4(th) examinations were also evaluated. During the 3 years, an increase in serum HDL cholesterol (2.7 mg/dl), and a reduction in the prevalence of hypertriglycemia detected with fasting blood samples (3.6%) and current smokers (5.4%) were observed in the intervention group. The mean HDL cholesterol level was significantly higher in the intervention group than in the control group at the 4th examination, reversed from the baseline survey. The serum non-HDL cholesterol level was significantly increased only in the control group. There was also a significant increase in the prevalence of hypertriglycemia nad high plasma glucose detected with fasting blood samples in the control group. The return participation rate after 3 years was 72.2% for the intervention group and 74.9% for the control group. The above-mentioned changes for risk factors were mainly due to returning participants at each examination. These interventional methods may be effective in improving overall cardiovascular risk factors in the population. However, the low return participation rate will dilute the effect of the intervention.


Headache improvement through TMD stabilization appliance and self-management therapies.
The purpose of this study was to assess headache response of unselected neurology clinic chronic headache patients to TMD stabilization appliance and self-management therapies, and to identify features of patients whose headaches are more likely to improve from these therapies. Twenty chronic headache patients in a nontreatment control period were provided appliance and self-management therapies, evaluated five weeks after therapy, and those who chose to continue using their appliances were evaluated three months later. The mean pretreatment Headache Disability Inventory (HDI) score of 64.5 suggested the headaches were severe. After five weeks, the mean HDI score decreased by 17 percent (p<0.003), headache medication consumption dropped by 18 percent (p<0.0001), and headache symptoms decreased by 19 percent (p<0.002). Comparing the three months with pretreatment follow-up, the fourteen participants who chose to continue using their appliances had a mean HDI score decrease of 23 percent (p<0.003), headache medication consumption drop of 46 percent (p<0.001), and headache symptom decrease of 39 percent (p<0.001). There was no correlation between response and headache type (p=0.722). These results suggest appliance and self-management therapies can be beneficial for many severe headache patients, irrespective of the headache type (tension-type, migraine without aura, and migraine with aura).


Understanding consumer decisions using behavioral economics.
Consumers make many decisions in everyday life involving finances, food, and health. It is known from behavioral economics research that people are often driven by short-term gratification, that is, people tend to choose the immediate, albeit smaller reward. But choosing the delayed reward, that is, delaying the gratification, can actually be beneficial. How can we motivate consumers to resist the "now" and invest in their future, leading to sustainable or healthy habits? We review recent developments from behavioral and neuroimaging studies that are relevant for understanding consumer decisions. Further, we present results from our field research that examined whether we can increase the perceived value of a (delayed) environmental benefit using tailored communication, that is, change the way it is framed. More specifically, we investigated whether we can boost the value of an abstract, long-term "green" claim of a product by expressing it as a concrete, short-term benefit. This is a new application area for behavioral economics.


Natural exposure to cutaneous anthrax gives long-lasting T cell immunity encompassing infection-specific epitopes.
There has been a long history of defining T cell epitopes to track viral immunity and to design rational vaccines, yet few data of this type exist for bacterial infections. Bacillus anthracis, the causative agent of anthrax, is both an endemic pathogen in many regions and a potential biological warfare threat. T cell immunity in naturally infected anthrax patients has not previously been characterized, which is surprising given concern about the ability of anthrax toxins to subvert or ablate adaptive immunity. We investigated CD4 T cell responses in patients from the Kayseri region of Turkey who were previously infected with cutaneous anthrax. Responses to B. anthracis protective Ag and lethal factor (LF) were investigated at the protein, domain, and epitope level. Several years after antibiotic-treated anthrax infection, strong T cell memory was detectable, with no evidence of the expected impairment in specific immunity. Although serological responses to existing anthrax vaccines focus primarily on protective Ag, the major target of T cell immunity in infected individuals and anthrax-vaccinated donors was LF, notably domain IV. Some of these anthrax epitopes showed broad binding to several HLA class alleles, but others were more constrained in their HLA binding patterns. Of specific CD4 T cell epitopes targeted within LF domain IV, one is preferentially seen in the context of bacterial infection, as opposed to vaccination, suggesting that studies of this type will be important in understanding how the human immune system confronts serious bacterial infection.


Rectal ketamine and midazolam for premedication in pediatric dentistry.
Rectally administered midazolam (0.30 mg/kg) and ketamine (5 mg/kg) were compared for preanesthetic medication in children undergoing dental extractions. Sixty patients between the ages 2 and 9 years were randomly allocated to three groups in this double-blind study. In one group of patients who received ketamine rectally, intravenous midazolam (0.05 mg/kg) also was administered immediately after induction of anesthesia. The results from this trial show that 30 minutes after rectal administration of the two drugs, good anxiolysis, sedation, and cooperation were obtained in most patients. Although midazolam appeared to be marginally more efficacious than ketamine in the majority of assessments made and seemed to have less adverse effects, no statistically significant differences could be shown. Ketamine showed a slight decrease and midazolam a slight increase in average blood pressures after premedication. These blood pressure differences were, however, considered to be of little clinical importance.


Association analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in systemic lupus erythematosus families: increased T allele frequency in systemic lupus erythematosus patients with autoimmune thyroid disease.
Recent case-control studies show associations of the minor T allele (of the C1858T single-nucleotide polymorphism corresponding to the R620W amino acid substitution) of PTPN22 with multiple autoimmune diseases, including systemic lupus erythematosus (SLE). We performed family-based association studies of this polymorphism in 4 independent cohorts containing SLE patients and their parents and/or other family members. A total of 2,689 individuals from 902 independent Caucasian families with SLE were genotyped using polymerase chain reaction pyrosequencing (cohorts 1 and 2) and the Sequenom MassArray system (cohorts 3 and 4). The transmission disequilibrium test (TDT) and the pedigree disequilibrium test (PDT) were conducted to assess the evidence of association. The 1858 C > T allele frequencies of the parents showed no deviation from Hardy-Weinberg equilibrium within each cohort. No evidence of preferential transmission of the T allele from heterozygous parents to their affected offspring was observed in each of the 4 cohorts or in the combined sample. Consistent with the TDT result, the PDT analysis revealed no significant association between the T allele and SLE. In 54 of the 661 SLE patients (cohorts 1 and 3) with documented autoimmune thyroid disease, the T allele frequency was higher than in individuals with SLE alone (16.7% versus 8.5%; P = 0.008, odds ratio 2.16 [95% confidence interval 1.25-3.72]). The R620W polymorphism of the PTPN22 gene is not a major risk allele for SLE susceptibility in our sample of Caucasian individuals from northern America, the UK, or Finland, but it appears to be a risk factor for the concurrent autoimmune diseases of autoimmune thyroid disease and SLE.


Antennally mediated negative feedback regulation of pheromone production in the pine engraver beetle, Ips pini.
Bark beetles use monoterpenoid aggregation pheromones to coordinate host colonization and mating. These chemical signals are produced de novo in midgut cells via the mevalonate pathway, and pheromone production may be regulated by a negative feedback system mediated through the antennae. In this study, we explored the effect of antennectomy on pheromone production and transcript levels of key mevalonate pathway genes in juvenile hormone III-treated male pine engraver beetles, Ips pini (Say). Antennectomized males produced significantly greater amounts of pheromone than podectomized males and those with intact antennae. Likewise, mRNA levels of three mevalonate pathway genes important in pheromone biosynthesis were measured by quantitative real-time PCR and found to be induced to a greater extent with antennectomy, suggesting a transcriptional regulation of pheromone production.


The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia.
Glucocorticoids are used in the curative treatment of acute lymphoblastic leukemia (ALL). Resistance to glucocorticoids is an important adverse prognostic factor in newly diagnosed ALL patients but its mechanism is unknown. Because SWI/SNF complex-mediated chromatin remodeling is required for glucocorticoid transcriptional activity in vitro, we investigated whether expression of subunits of the SWI/SNF complex was related to glucocorticoid resistance in ALL. Gene expression and in vitro sensitivity to prednisolone and dexamethasone were assessed in a training set of primary ALL cells from 177 children with newly diagnosed ALL and a validation set of cells from an independent cohort of 95 ALL patients. The global test method was used to select pathways whose genes were associated with drug sensitivity. Genes involved in chromatin remodeling were identified by use of the Gene Ontology database. Short hairpin RNA (shRNA) was used to knock down mRNA expression of SMARCA4 in glucocorticoid-sensitive Jurkat human ALL cells. Spearman rank correlation, multiple linear regression, and logistic regression were used to investigate associations between gene expression and glucocorticoid sensitivity. All statistical tests were two-sided. Statistically significant associations between decreased expression in ALL cells of genes for core subunits of the SWI/SNF complex-SMARCA4, ARID1A, and SMARCB1-and resistance to prednisolone and dexamethasone were identified in the training cohort. In the validation cohort, expression of SMARCA4 (P < .001 and r = -0.43), ARID1A (P = .016 and r = -0.29), and SMARCB1 (P = .019 and r = -0.29) in ALL cells was statistically significantly associated with dexamethasone sensitivity, and SMARCA4 expression (P = .018 and r = -0.28) was statistically significantly associated with prednisolone sensitivity. Prednisolone resistance was higher in SMARCA4 shRNA-transfected Jurkat cells (drug concentration lethal to 50% of the leukemia cells [LC(50)] = 277 microM) than in control shRNA-transfected cells (LC(50) = 174 microM, difference = 103 microM, 95% confidence interval of the difference = 100 to 106 microM; P < .001, t test). Decreased expression of as many as three subunits of the SWI/SNF complex appears to be associated with glucocorticoid resistance in primary ALL cells.


Effect of Lactobacillus salivarius bacteriocin Abp118 on the mouse and pig intestinal microbiota.
Lactobacilli are gram-positive bacteria that are a subdominant element in the human gastrointestinal microbiota, and which are commonly used in the food industry. Some lactobacilli are considered probiotic, and have been associated with health benefits. However, there is very little culture-independent information on how consumed probiotic microorganisms might affect the entire intestinal microbiota. We therefore studied the impact of the administration of Lactobacillus salivarius UCC118, a microorganism well characterized for its probiotic properties, on the composition of the intestinal microbiota in two model animals. UCC118 has anti-infective activity due to production of the bacteriocin Abp118, a broad-spectrum class IIb bacteriocin, which we hypothesized could impact the microbiota. Mice and pigs were administered wild-type (WT) L. salivarius UCC118 cells, or a mutant lacking bacteriocin production. The microbiota composition was determined by pyrosequencing of 16S rRNA gene amplicons from faeces. The data show that L. salivarius UCC118 administration had no significant effect on proportions of major phyla comprising the mouse microbiota, whether the strain was producing bacteriocin or not. However, L. salivarius UCC118 WT administration led to a significant decrease in Spirochaetes levels, the third major phylum in the untreated pig microbiota. In both pigs and mice, L. salivarius UCC118 administration had an effect on Firmicutes genus members. This effect was not observed when the mutant strain was administered, and was thus associated with bacteriocin production. Surprisingly, in both models, L. salivarius UCC118 administration and production of Abp118 had an effect on gram-negative microorganisms, even though Abp118 is normally not active in vitro against this group of microorganisms. Thus L. salivarius UCC118 administration has a significant but subtle impact on mouse and pig microbiota, by a mechanism that seems at least partially bacteriocin-dependent.


Posterior atlantoaxial stabilization: new alternative to C1-2 transarticular screws.
Surgical treatment of atlantoaxial instability has evolved to include various posterior wiring techniques including Brooks, Gallie, and Sonntag fusions in which success rates range from 60 to 100%. The Magerl-Seemans technique in which C1-2 transarticular screws are placed results in fusion rates between 87 and 100%. This procedure is technically demanding and requires precise knowledge of the course of the vertebral arteries (VAs). The authors introduce a new C1-2 fixation procedure in which C-1 lateral mass and C-2 pedicle screws are placed that may have advantages over C1-2 transarticular screw constructs. A standard posterior C1-2 exposure is obtained. Polyaxial C-2 pedicle screws and C-1 lateral mass screws are placed bilaterally. Rods are connected to the screws and secured using locking nuts. A cross-link is then placed. Fusion can be performed at the atlantoaxial joint by elevating the C-2 nerve root. The technique for this procedure has been used in four cases of atlantoaxial instability at the author's institution. There have been no C-2 nerve root- or VA-related injuries. No cases of construct failure have been observed in the short-term follow up period. Atlantoaxial lateral mass and axial pedicle screw fixation offers an alternative means of achieving atlantoaxial fusion. The technique is less demanding than that required for transarticular screw placement and may avoid the potential complication of VA injury. The cross-linked construct is theoretically stable in flexion, extension, and rotation. Laminectomy or fracture of the posterior elements does not preclude use of this fixation procedure.


De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.
Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.


Optical theory of partially coherent thin-film energy-absorbing structures for power detectors and imaging arrays.
Free-space power detectors often have energy absorbing structures comprising multilayer systems of patterned thin films. We show that for any system of interacting resistive films, the expectation value of the absorbed power is given by the contraction of two tensor fields: one describes the spatial state of coherence of the incoming radiation, the other the state of coherence to which the detector is sensitive. Equivalently, the natural modes of the optical field scatter power into the natural modes of the detector. We describe a procedure for determining the amplitude, phase, and polarization patterns of a detector's optical modes and their relative responsivities. The procedure gives the state of coherence of the currents flowing in the system and leads to important conceptual insights into the way the pixels of an imaging array interact and extract information from an optical field.


Human rights and HIV/AIDS in the context of 3 by 5: time for new directions?
Over the last decade, the success of the human rights-based approach to HIV/AIDS has been spotty, says Mark Heywood. In this feature article, the author describes the challenges that remain in implementing a human rights approach. He presents an analysis of questions raised by De Cock et al concerning the applicability of the human rights approach. The author argues that human rights advocacy needs to continue, but that new directions are required. The article outlines new directions in the areas of (a) confidentiality and openness, (b) HIV testing, and (c) health systems. The author concludes that the most serious threat to human rights remains the unwillingness of national governments to take all necessary measures to build health services and prevent epidemics.


The role of uPAR in epithelial-mesenchymal transition in small airway epithelium of patients with chronic obstructive pulmonary disease.
Epithelial-mesenchymal transition (EMT) plays a crucial role in small airway fibrosis of patients with chronic obstructive pulmonary disease (COPD). Increasing evidence suggests that the urokinase plasminogen activator receptor (uPAR) is involved in the pathogenesis of COPD. Increased uPAR expression has been implicated in the promotion of EMT in numerous cancers; however the role of uPAR in EMT in small airway epithelial cells of patients with COPD remains unclear. In this study, we investigated the degree of EMT and uPAR expression in lung epithelium of COPD patients, and verified the effect of uPAR on cigarette smoke extract (CSE)-induced EMT in vitro. The expression of EMT biomarkers and uPAR was assessed in lung epithelium specimens from non-smokers (n = 25), smokers (n = 25) and non-smokers with COPD (n = 10) and smokers with COPD (n = 18). The role of uPAR on CSE-induced EMT in human small airway epithelial cells (HSAEpiCs) was assessed by silencing uPAR expression in vitro. Markers of active EMT and uPAR expression were significantly increased in the small airway epithelium of patients with COPD compared with controls. We also observed a significant correlation between uPAR and vimentin expression in the small airway epithelium. In vitro, CSE-induced EMT in HSAEpiCs was associated with high expression of uPAR, and targeted silencing of uPAR using shRNA inhibited CSE-induced EMT. Finally, we demonstrate that the PI3K/Akt signaling pathway is required for uPAR-mediated EMT in HSAEpiCs. A uPAR-dependent signaling pathway is required for CSE-induced EMT, which contributes to small airway fibrosis in COPD. We propose that increased uPAR expression in the small airway epithelium of patients with COPD participates in an active EMT process.


Health insurance status, cost-related medication underuse, and outcomes among diabetes patients in three systems of care.
Chronically ill patients often experience difficulty paying for their medications and, as a result, use less than prescribed. The objectives of this study were to determine the relationship between patients with diabetes' health insurance coverage and cost-related medication underuse, the association between cost-related underuse and health outcomes, and the role of comorbidity in this process. We used a patient survey with linkage to insurance information and hemoglobin A1C (A1C) test results. We studied 766 adults with diabetes recruited from 3 Veterans Affairs (VA), 1 county, and 1 university healthcare system. Main outcomes consisted of self-reported medication underuse as a result of cost, A1C levels, symptom burden, and Medical Outcomes Study 12-Item Short-Form physical and mental functioning scores. Fewer VA patients reported cost-related medication underuse (9%) than patients with private insurance (18%), Medicare (25%), Medicaid (31%), or no health insurance (40%; P <0.0001). Underuse was substantially more common among patients with multiple comorbid chronic illnesses, except those who used VA care. The risk of cost-related underuse for patients with 3+ comorbidities was 2.8 times as high among privately insured patients as VA patients (95% confidence interval, 1.2-6.5), and 4.3 to 8.3 times as high among patients with Medicare, Medicaid, or no insurance. Individuals reporting cost-related medication underuse had A1C levels that were substantially higher than other patients (P <0.0001), more symptoms, and poorer physical and mental functioning (all P <0.05). Many patients with diabetes use less of their medication than prescribed because of the cost, and those reporting cost-related adherence problems have poorer health. Cost-related adherence problems are especially common among patients with diabetes with comorbid diseases, although the VA's drug coverage may protect patients from this increased risk.


Photobiomodulation preserves behaviour and midbrain dopaminergic cells from MPTP toxicity: evidence from two mouse strains.
We have shown previously that near-infrared light (NIr) treatment or photobiomodulation neuroprotects dopaminergic cells in substantia nigra pars compacta (SNc) from degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Balb/c albino mice, a well-known model for Parkinson's disease. The present study explores whether NIr treatment offers neuroprotection to these cells in C57BL/6 pigmented mice. In addition, we examine whether NIr influences behavioural activity in both strains after MPTP treatment. We tested for various locomotive parameters in an open-field test, namely velocity, high mobility and immobility. Balb/c (albino) and C57BL/6 (pigmented) mice received injections of MPTP (total of 50 mg/kg) or saline and NIr treatments (or not) over 48 hours. After each injection and/or NIr treatment, the locomotor activity of the mice was tested. After six days survival, brains were processed for TH (tyrosine hydroxylase) immunochemistry and the number of TH⁺ cells in the substantia nigra pars compacta (SNc) was estimated using stereology. Results showed higher numbers of TH⁺ cells in the MPTP-NIr groups of both strains, compared to the MPTP groups, with the protection greater in the Balb/c mice (30% vs 20%). The behavioural tests revealed strain differences also. For Balb/c mice, the MPTP-NIr group showed greater preservation of locomotor activity than the MPTP group. Behavioural preservation was less evident in the C57BL/6 strain however, with little effect of NIr being recorded in the MPTP-treated cases of this strain. Finally, there were differences between the two strains in terms of NIr penetration across the skin and fur. Our measurements indicated that NIr penetration was considerably less in the pigmented C57BL/6, compared to the albino Balb/c mice. In summary, our results revealed the neuroprotective benefits of NIr treatment after parkinsonian insult at both cellular and behavioural levels and suggest that Balb/c strain, due to greater penetration of NIr through skin and fur, provides a clearer model of protection than the C57BL/6 strain.


Characterization of a cyanobacterial-like uptake [NiFe] hydrogenase: EPR and FTIR spectroscopic studies of the enzyme from Acidithiobacillus ferrooxidans.
Electron paramagnetic resonance (EPR) and Fourier transform IR studies on the soluble hydrogenase from Acidithiobacillus ferrooxidans are presented. In addition, detailed sequence analyses of the two subunits of the enzyme have been performed. They show that the enzyme belongs to a group of uptake [NiFe] hydrogenases typical for Cyanobacteria. The sequences have also a close relationship to those of the H(2)-sensor proteins, but clearly differ from those of standard [NiFe] hydrogenases. It is concluded that the structure of the catalytic centre is similar, but not identical, to that of known [NiFe] hydrogenases. The active site in the majority of oxidized enzyme molecules, 97% in cells and more than 50% in the purified enzyme, is EPR-silent. Upon contact with H(2) these sites remain EPR-silent and show only a limited IR response. Oxidized enzyme molecules with an EPR-detectable active site show a Ni(r)*-like EPR signal which is light-sensitive at cryogenic temperatures. This is a novelty in the field of [NiFe] hydrogenases. Reaction with H(2) converts these active sites to the well-known Ni(a)-C* state. Illumination below 160 K transforms this state into the Ni(a)-L* state. The reversal, in the dark at 200 K, proceeds via an intermediate Ni EPR signal only observed with the H(2)-sensor protein from Ralstonia eutropha. The EPR-silent active sites in as-isolated and H(2)-treated enzyme are also light-sensitive as observed by IR spectra at cryogenic temperatures. The possible origin of the light sensitivity is discussed. This study represents the first spectral characterization of an enzyme of the group of cyanobacterial uptake hydrogenases.


Evaluating the impact of screening plus eave tubes on malaria transmission compared to current best practice in central Côte d'Ivoire: a two armed cluster randomized controlled trial.
Access to long-lasting insecticidal nets (LLINs) has increased and malaria has decreased globally, but malaria transmission remains high in parts of sub-Saharan Africa and insecticide resistance threatens current progress. Eave tubes are a new tool for the targeted delivery of insecticides against mosquitoes attempting to enter houses. The primary objective of this trial is to test whether screening plus eave tubes (SET) provides protection against malaria, on top of universal coverage with LLINs in an area of intense pyrethroid resistance. The trial will also assess acceptability and cost-effectiveness of the intervention. A two-armed, cluster randomized controlled trial will be conducted to evaluate the effect of SET on clinical malaria incidence in children living in central Côte d'Ivoire. Forty villages will be selected based on population size and the proportion of houses suitable for modification with SET. Using restricted randomization, half the villages will be assigned to the treatment arm (SET + LLINs) and the remainder will be assigned to the control arm (LLINs only). In both arms, LLINs will be distributed and in the treatment arm, householders will be offered SET. Fifty children aged six months to eight years old will be enrolled from randomly selected households in each of the 40 villages. Cohorts will be cleared of malaria parasites at the start of the study and one year after recruitment, and will be monitored for clinical malaria case incidence by active case detection over two years. Mosquito densities will be assessed using CDC light traps and human landing catches and a subset of Anopheles mosquitoes will be examined for parity status and tested for sporozoite infection. Acceptability of SET will be monitored using surveys and focus groups. Cost-effectiveness analysis will measure the incremental cost per case averted and per disability-adjusted life year (DALY) averted of adding SET to LLINs. Economic and financial costs will be estimated from societal and provider perspective using standard economic evaluation methods. This study will be the first evaluation of the epidemiological impact of SET. Trial findings will show whether SET is a viable, cost-effective technology for malaria control in Côte d'Ivoire and possibly elsewhere. ISRCTN18145556 , registered on 01 February 2017 - retrospectively registered.