Factors associated with home delivery in Bahirdar, Ethiopia: a case control study.
In Ethiopia although pregnant mothers increasingly attend antenatal clinics, utilization of skilled delivery service remains very low. The individual or health system factors that affect women's preferences for delivery places are not well known. A case control study was conducted in July 2010 to assess factors associated with utilization of institutional delivery service. A total of 324 mothers who recently delivered and visited either postnatal care or sought immunization services were included. Cases (n = 108) were mothers who gave birth at home and controls (n = 216) were those who delivered at health facility. Pre-tested and standardized questionnaires were used to collect relevant data by trained data collectors. Logistic regression model was used to control for confounding. The likelihood of delivering at home was greater among mothers with inadequate knowledge of pregnancy related services (AOR = 62, 95% CI: 3, 128.4), those who started attending ANC after 24 weeks of gestation (AOR 8.7, 95% CI: 2.2, 33.3), mothers having no formal education (Adjusted OR 4.2, 95% CI 1.63, 11.27) and rural residents (AOR = 3.6, 95%CI: 1.4, 9.0). The predominant factors associated with home delivery services were lack of knowledge about obstetrics care, delay in starting Antenatal Care (ANC) follow up, having, Illiteracy and rural residence. Audience specific behavioral change communication should be designed to improve the demand for delivery services. Health professionals should take the opportunity to encourage mothers attend delivery services during ANC follow up. Improvements should be made in social conditions including literacy and major social mobilization endeavors.


Multifunctionality of structural nanohybrids: the crucial role of carbon nanotube covalent and non-covalent functionalization in enabling high thermal, mechanical and self-healing performance.
This study proposes new kinds of functionalization procedures able to preserve specific properties of carbon nanotubes (CNTs) and to improve compatibility with the epoxy matrix. Through a covalent approach, for the first time, CNTs are functionalized with the same hardener agent, 4,4'-diaminodiphenyl sulfone, employed to solidify the epoxy matrix and capable to fulfill mechanical requirements of industrial structural resins. The same CNTs are non-covalently modified through the polymer wrapping mechanism with benzoxazine (Bz) terminated polydimethylsiloxane (PDMS). The comparison between electrical and mechanical properties of the nanocomposites highlights the success of the non-covalent functionalization in determining an increase in the glass transition temperature (Tg) and in better preserving the unfunctionalized CNT electrical conductivity. Besides, tunneling atomic force microscopy (TUNA), powerful to catch ultra-low currents, has been used for revealing the morphology on nanoscale domains and detecting the conductivity on the same location of CNT/epoxy resins. No electrical contacts to the grounds have been used for the TUNA analysis; a procedure that does not alter the results on the interface domains which experience contact areas with strong differences in their properties. The effectiveness of performed CNT functionalizations as a route to impart self-healing efficiency to the resin formulations has also been proved.


Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study.
We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.


Empirical assessment of the impact of sample number and read depth on RNA-Seq analysis workflow performance.
RNA-Sequencing analysis methods are rapidly evolving, and the tool choice for each step of one common workflow, differential expression analysis, which includes read alignment, expression modeling, and differentially expressed gene identification, has a dramatic impact on performance characteristics. Although a number of workflows are emerging as high performers that are robust to diverse input types, the relative performance characteristics of these workflows when either read depth or sample number is limited-a common occurrence in real-world practice-remain unexplored. Here, we evaluate the impact of varying read depth and sample number on the performance of differential gene expression identification workflows, as measured by precision, or the fraction of genes correctly identified as differentially expressed, and by recall, or the fraction of differentially expressed genes identified. We focus our analysis on 30 high-performing workflows, systematically varying the read depth and number of biological replicates of patient monocyte samples provided as input. We find that, in general for most workflows, read depth has little effect on workflow performance when held above two million reads per sample, with reduced workflow performance below this threshold. The greatest impact of decreased sample number is seen below seven samples per group, when more heterogeneity in workflow performance is observed. The choice of differential expression identification tool, in particular, has a large impact on the response to limited inputs. Among the tested workflows, the recall/precision balance remains relatively stable at a range of read depths and sample numbers, although some workflows are more sensitive to input restriction. At ranges typically recommended for biological studies, performance is more greatly impacted by the number of biological replicates than by read depth. Caution should be used when selecting analysis workflows and interpreting results from low sample number experiments, as all workflows exhibit poorer performance at lower sample numbers near typically reported values, with variable impact on recall versus precision. These analyses highlight the performance characteristics of common differential gene expression workflows at varying read depths and sample numbers, and provide empirical guidance in experimental and analytical design.


Children raised in fatherless families from infancy: a follow-up of children of lesbian and single heterosexual mothers at early adolescence.
An increasing number of lesbian women and single heterosexual women are bringing up children with no male involvement. This study follows up to adolescence a sample of children raised in fatherless families from birth or early infancy. Twenty-five lesbian mother families and 38 families headed by a single heterosexual mother were compared with 38 two-parent heterosexual families. The quality of parenting by the mother, and the social and emotional development of the child, were assessed using standardised interview and questionnaire measures administered to mothers, children and teachers. Children in fatherless families experienced more interaction with their mother, and perceived her as more available and dependable than their peers from father-present homes. However, there were no group differences in maternal warmth towards the children. Mothers raising their child without a father reported more severe disputes with their child than did mothers in father-present families. The children's social and emotional development was not negatively affected by the absence of a father, although boys in father-absent families showed more feminine but no less masculine characteristics of gender role behaviour. No major differences in parenting or child development were identified between families headed by lesbian and single heterosexual mothers. The presence or absence of a father in the home from the outset does appear to have some influence on adolescents' relationships with their mothers. However, being without a resident father from infancy does not seem to have negative consequences for children. In addition, there is no evidence that the sexual orientation of the mother influences parent-child interaction or the socioemotional development of the child.


Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes.
Pluripotent-cell-derived cardiomyocytes have great potential for use in research and medicine, but limitations in their maturity currently constrain their usefulness. Here, we report a method for improving features of maturation in murine and human embryonic-stem-cell-derived cardiomyocytes (m/hESC-CMs). We found that coculturing m/hESC-CMs with endothelial cells improves their maturity and upregulates several microRNAs. Delivering four of these microRNAs, miR-125b-5p, miR-199a-5p, miR-221, and miR-222 (miR-combo), to m/hESC-CMs resulted in improved sarcomere alignment and calcium handling, a more negative resting membrane potential, and increased expression of cardiomyocyte maturation markers. Although this could not fully phenocopy all adult cardiomyocyte characteristics, these effects persisted for two months following delivery of miR-combo. A luciferase assay demonstrated that all four miRNAs target ErbB4, and siRNA knockdown of ErbB4 partially recapitulated the effects of miR-combo. In summary, a combination of miRNAs induced via endothelial coculture improved ESC-CM maturity, in part through suppression of ErbB4 signaling.


Molecular insights into androgen actions in male and female reproductive function from androgen receptor knockout models.
Androgens and the androgen receptor (AR) have well known roles in male reproduction, and recent genetic mouse models inactivating the Ar gene have conclusively defined a role for androgens in female reproduction. In males, AR gene inactivation severely disrupts spermatogenesis by interrupting completion of meiosis, thereby eliminating production of mature sperm leading to male sterility. These effects have overshadowed the study of additional post-meiotic androgen effects required for the production of fully functional spermatozoa, as well as the production of females with complete androgen insensitivity which cannot be produced by natural breeding. However, these limitations have been overcome by the creation of global and cell-specific AR knockout (ARKO) mouse models using Cre-LoxP genetic engineering. Pubmed searches were carried out using the following search terms: androgen receptor, knockout mouse and fertility. Articles published before the end of November 2009 were included. These experimental models have identified cell-specific AR-mediated androgen actions in testis and androgen actions in sex accessory glands independent of testicular effects which are crucial for sperm maturation, motion and fertilizing ability. The ability to produce homozygous ARKO females has revealed that AR-mediated androgen actions are important for normal female fertility. AR function is required for full functionality in follicle health, development and ovulation through both intra-ovarian and neuroendocrine mechanisms. ARKO mouse models provide valuable tools to unravel novel roles of AR-mediated actions in male and female reproductive function, and new insights into the role of androgens in human reproductive function.


UDP-glucuronyltransferase. Report on the workshop conference of the German Society for Clinical Chemistry held on September 27-28, 1977 in Schloss Auel.
A Workshop Conference on UDP-glucuronyltransferase was held in order to bring together different investigators specialising in a particular aspect of the enzyme. The intention was to find a basis for a closer cooperation between the different groups and to exchange ideas and methods making it possible to cross the hurdles facing those who work in the field of glucuronidation of endogenous and exogenous substances. The topics which were chosen for the meeting covered the following aspects: methods of determination of UDP-glucuronyltransferase activity; problems relating to the origin of the enzyme and the nature of the substrate; application of assays of UDP-glucuronyltransferase in clinical chemistry; enzyme-substrate interactions and factors influencing the enzymic reaction; the role of UDP-glucuronyltransferase in the entero-hepatic circulation of glucuronides, regulation and induction of UDP-glucuronyltransferase, with a subsection on solubilisation and purification.


The HELLP syndrome: clinical issues and management. A Review.
The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 0.5 to 0.9% of all pregnancies and in 10-20% of cases with severe preeclampsia. The present review highlights occurrence, diagnosis, complications, surveillance, corticosteroid treatment, mode of delivery and risk of recurrence. Clinical reports and reviews published between 2000 and 2008 were screened using Pub Med and Cochrane databases. About 70% of the cases develop before delivery, the majority between the 27th and 37th gestational weeks; the remainder within 48 hours after delivery. The HELLP syndrome may be complete or incomplete. In the Tennessee Classification System diagnostic criteria for HELLP are haemolysis with increased LDH (> 600 U/L), AST (>or= 70 U/L), and platelets < 100 x 10(9)/L. The Mississippi Triple-class HELLP System further classifies the disorder by the nadir platelet counts. The syndrome is a progressive condition and serious complications are frequent. Conservative treatment (>or= 48 hours) is controversial but may be considered in selected cases < 34 weeks' gestation. Delivery is indicated if the HELLP syndrome occurs after the 34th gestational week or the foetal and/or maternal conditions deteriorate. Vaginal delivery is preferable. If the cervix is unfavourable, it is reasonable to induce cervical ripening and then labour. In gestational ages between 24 and 34 weeks most authors prefer a single course of corticosteroid therapy for foetal lung maturation, either 2 doses of 12 mg betamethasone 24 hours apart or 6 mg or dexamethasone 12 hours apart before delivery. Standard corticosteroid treatment is, however, of uncertain clinical value in the maternal HELLP syndrome. High-dose treatment and repeated doses should be avoided for fear of long-term adverse effects on the foetal brain. Before 34 weeks' gestation, delivery should be performed if the maternal condition worsens or signs of intrauterine foetal distress occur. Blood pressure should be kept below 155/105 mmHg. Close surveillance of the mother should be continued for at least 48 hours after delivery.


Delayed effects of tamoxifen in hepatocarcinogenesis-resistant Fischer 344 rats as compared with susceptible strains.
The anti-oestrogenic drug tamoxifen has been under investigation as a breast cancer chemopreventive agent for at least a decade. However, its use for this purpose is still debatable since it is able to induce liver tumours in rats via a mechanism involving metabolic activation to a DNA adduct-forming electrophilic intermediate. The metabolic activation and adduct-forming properties of tamoxifen are now well characterized but less is known about its ability to induce hepatic cell proliferation, which is also essential for the carcinogenic process. The effects of tamoxifen on liver weight and cell proliferation were compared in female Fischer 344 (F344), Wistar and Lewis rats given the drug in the diet for up to 26 weeks. The onset and duration of hepatic cell proliferation varied between the strains of rat. In Wistar and Lewis but not F344 rats there was a marked increase in hepatocellular proliferation during the first 4 weeks of tamoxifen administration. In the Wistar strain this was associated with an increase in DNA adduct levels; no such increase was observed in the F344 strain. The onset of the proliferative response was delayed until the 13 week time point in the F344 strain. By the 13 and 26 week time points, cell proliferation in tamoxifen-treated Wistar and Lewis rat liver had returned to normal, but the amount of apoptotic activity in these livers was elevated. This suggests that excess cells generated during the proliferative phase of tamoxifen treatment were being eliminated by apoptosis. In the F344 strain, however, increased proliferative activity was associated with relatively low apoptotic activity at the 26 week time point, suggesting that the delayed proliferative response had yet to be balanced by apoptotic deletion. This is consistent with the fact that tamoxifen-induced hepatocellular tumours develop very late, towards the end of the lifespan, in this strain. The cell proliferative activity of tamoxifen in the Wistar rat liver was compared with that of a non-mutagenic analogue, toremifene. Tamoxifen induced increased cell cycle activity in the livers of rats following gavage dosing at all sampling times (1-12 weeks), whereas toremifene had no effect on the incidence of cycling in hepatic cells, demonstrating that the hepatic cell proliferation is not a general response to anti-oestrogen treatment. These observations suggest that the rate of promotion of liver tumours by tamoxifen is a function of the rate, time of onset and duration of increased cell replication. The susceptibility of rat strains to the hepatocarcinogenic effects of tamoxifen appears to depend upon the balance between initiation via DNA adduct formation, promotion via increased cell proliferation and cell deletion via apoptosis. Our findings suggest that an early proliferative response to tamoxifen is important in this process.


Proteomic analysis of Salmonella enterica serovar typhimurium isolated from RAW 264.7 macrophages: identification of a novel protein that contributes to the replication of serovar typhimurium inside macrophages.
To evade host resistance mechanisms, Salmonella enterica serovar Typhimurium (STM), a facultative intracellular pathogen, must alter its proteome following macrophage infection. To identify new colonization and virulence factors that mediate STM pathogenesis, we have isolated STM cells from RAW 264.7 macrophages at various time points following infection and used a liquid chromatography-mass spectrometry-based proteomic approach to detect the changes in STM protein abundance. Because host resistance to STM infection is strongly modulated by the expression of a functional host-resistant regulator, i.e. natural resistance-associated macrophage protein 1 (Nramp1, also called Slc11a1), we have also examined the effects of Nramp1 activity on the changes of STM protein abundances. A total of 315 STM proteins have been identified from isolated STM cells, which are largely housekeeping proteins whose abundances remain relatively constant during the time course of infection. However, 39 STM proteins are strongly induced after infection, suggesting their involvement in modulating colonization and infection. Of the 39 induced proteins, 6 proteins are specifically modulated by Nramp1 activity, including STM3117, as well as STM3118-3119 whose time-dependent abundance changes were confirmed using Western blot analysis. Deletion of the gene encoding STM3117 resulted in a dramatic reduction in the ability of STM to colonize wild-type RAW 264.7 macrophages, demonstrating a critical involvement of STM3117 in promoting the replication of STM inside macrophages. The predicted function common for STM3117-3119 is biosynthesis and modification of the peptidoglycan layer of the STM cell wall.


Cowden syndrome complicated by schizophrenia: A first clinical report.
Patients with Cowden syndrome exhibit mucocutaneous lesions, hamartomatous polyposis of the gastrointestinal tract, and macrocephaly, often complicated by malignant tumors, such as breast, thyroid, and uterine cancers. Autism spectrum and epilepsy have been known as neuropsychiatric symptoms associated with Cowden syndrome; however, to the best of our knowledge, there is no report on cases complicated by schizophrenia. Here, we report a first case of Cowden syndrome complicated by schizophrenia. A 49-year-old Japanese woman started experiencing auditory hallucinations in her teens. She had left breast cancer at the age of 34 years, and right breast cancer at the age of 37 years, all of which were surgically treated. She was also being treated by oral medications for Hashimoto's disease. On consulting her previous doctor for abnormal uterine bleeding that lasted for a year, she was diagnosed with endometrial cancer. However, immediately before surgery, her auditory hallucinations and paranoid delusions became severe, and she was referred to our hospital for detailed examination and treatment. No abnormalities were found on head MRI, and she was diagnosed with schizophrenia on the basis of neuropsychiatric examination findings. After her psychiatric symptoms were controlled by 2 mg of risperidone, she underwent surgery for endometrial cancer. Although there was no apparent family history, physical findings including macrocephaly and papillomatous skin lesions together with her past medical history of multiple malignant tumors suggested Cowden syndrome. Postoperatively, genetic testing revealed a pathogenic variant c.655C > T; p. Gln219* (NM_000314.4) in PTEN, leading to the confirmation of the diagnosis of Cowden syndrome.


Impact of short-term exposure to fine particulate matter on emergency ambulance dispatches in Japan.
Evidence of an association between fine particulate matter (PM2.5) and morbidity is limited in Asia. We used a case-crossover design to evaluate the association between short-term exposure to PM2.5 and emergency ambulance dispatches (as a proxy of acute health outcomes), and to calculate the extent to which a 10 μg/m(3) decrease in PM2.5 concentrations would reduce the number of ambulance dispatches. We used data on emergency ambulance dispatches in Fukuoka City, Japan between 2005 and 2010. Emergency ambulance services are publicly funded and cover the entire city. After excluding ambulance dispatches related to external injuries and pregnancy/childbirth, we analysed data on the remaining 176 123 dispatches. We also collected records of daily concentrations of PM2.5 from one ambient air pollution monitoring station. ORs per 10 μg/m(3) increase in PM2.5 were estimated using conditional logistic regression controlled for ambient temperature and relative humidity. During the study period, the average daily concentration of PM2.5 was 20.3 μg/m(3). Exposure to PM2.5 was associated with emergency ambulance dispatches in general (lag0-1; OR=1.008 (95% CI 1.002 to 1.014)) and with dispatches due to respiratory diseases (lag0-1; OR=1.027 (1.007 to 1.048)). No association was observed for dispatches due to cardiovascular diseases. We estimated that a 10 μg/m(3) decrease in PM2.5 concentrations would have led to approximately 260 (estimated range=70-460) fewer ambulance dispatches in Fukuoka for 2012. Providing further evidence on the short-term health effects of PM2.5 exposure, we found that exposure was associated with an increased number of emergency ambulance dispatches. The effect was, however, relatively small.


Jam1a-Jam2a interactions regulate haematopoietic stem cell fate through Notch signalling.
Notch signalling plays a key role in the generation of haematopoietic stem cells (HSCs) during vertebrate development and requires intimate contact between signal-emitting and signal-receiving cells, although little is known regarding when, where and how these intercellular events occur. We previously reported that the somitic Notch ligands, Dlc and Dld, are essential for HSC specification. It has remained unclear, however, how these somitic requirements are connected to the later emergence of HSCs from the dorsal aorta. Here we show in zebrafish that Notch signalling establishes HSC fate as their shared vascular precursors migrate across the ventral face of the somite and that junctional adhesion molecules (JAMs) mediate this required Notch signal transduction. HSC precursors express jam1a (also known as f11r) and migrate axially across the ventral somite, where Jam2a and the Notch ligands Dlc and Dld are expressed. Despite no alteration in the expression of Notch ligand or receptor genes, loss of function of jam1a led to loss of Notch signalling and loss of HSCs. Enforced activation of Notch in shared vascular precursors rescued HSCs in jam1a or jam2a deficient embryos. Together, these results indicate that Jam1a-Jam2a interactions facilitate the transduction of requisite Notch signals from the somite to the precursors of HSCs, and that these events occur well before formation of the dorsal aorta.


Development of In Vitro Denture Biofilm Models for Halitosis Related Bacteria and their Application in Testing the Efficacy of Antimicrobial Agents.
Since dentures can serve as a reservoir for halitosis-causing oral bacteria, halitosis development is a concern for denture wearers. In this study, we surveyed the prevalence of four selected halitosis-related species (Fusobacterium nucleatum, Tannerella forsythia, Veillonella atypica and Klebsiella pneumoniae) in clinical denture plaque samples, and developed denture biofilm models for these species in vitro to facilitate assessment of antimicrobial treatment efficacy. Design : Denture plaque from ten healthy and ten denture stomatitis patients was screened for the presence of aforementioned four species by PCR. Biofilm formation by these halitosis-associated species on the surfaces of denture base resin (DBR) discs was evaluated by crystal violet staining and confocal laser scanning microscopy. The efficacy of denture cleanser treatment on these mono-species biofilms was evaluated by colony counting. Results : 80% of the subjects in the denture stomatitis group and 60% in the healthy group contained at least one of the targeted halitosis-related species in their denture plaque. All halitosis species tested were able to form biofilms on DBR disc surfaces to varying degrees. These in vitro mono-species resin biofilm models were used to evaluate the efficacy of denture cleansers, which exhibited differential efficacies. When forming biofilms on resin surfaces, the halitosis-related species displayed enhanced resistance to denture cleansers compared with their planktonic counterparts. Conclusion : The four selected halitosis-related bacterial species examined in this study are present on the majority of dentures. The mono-species biofilm models established on DBR discs for these species are an efficient screening tool for dental product evaluation.


Pathways linking obesity to health-related quality of life.
Obesity is a well-recognized risk factor for impaired health-related quality of life (HRQOL). Nevertheless, few studies have investigated the mechanisms underlying the obesity-HRQOL associations. In this study, we explored potential mediators of the associations between obesity and HRQOL. Body mass index (BMI), an indicator of obesity, and HRQOL data were available for the 34,565 individuals 20 years of age and older participating in the cross-sectional Korea National Health and Nutrition Examination Survey 2007-2012. HRQOL was measured by the EuroQol five-dimension descriptive system. Path analysis was performed to assess the contributions of obesity-related diseases and self-rated health (SRH) on the relationships between obesity and HRQOL. In men, obesity was negatively associated with HRQOL through diabetes mellitus, hypertension, and dyslipidemia and positively associated with HRQOL through SRH. These opposite indirect effects offset one another and produced a non-significant association between obesity and HRQOL in men. However, in women, obesity was directly associated with HRQOL and indirectly associated with HRQOL through diabetes mellitus and SRH. Since these associations were in the same negative direction, the negative obesity-HRQOL association was clearly observed in women. Obesity was negatively associated with HRQOL through obesity-related diseases in both genders. However, in men, the positive association between obesity and SRH resulted in a non-significant association of obesity with HRQOL.


Autophagy in healthy aging and disease.
Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health.


Sequential bioavailability of sedimentary organic matter to heterotrophic bacteria.
Aquatic sediments harbour diverse microbial communities that mediate organic matter degradation and influence biogeochemical cycles. The pool of bioavailable carbon continuously changes as a result of abiotic processes and microbial activity. It remains unclear how microbial communities respond to heterogeneous organic matrices and how this ultimately affects heterotrophic respiration. To explore the relationships between the degradation of mixed carbon substrates and microbial activity, we incubated batches of organic-rich sediments in a novel bioreactor (IsoCaRB) that permitted continuous observations of CO2 production rates, as well as sequential sampling of isotopic signatures (δ13 C, Δ14 C), microbial community structure and diversity, and extracellular enzyme activity. Our results indicated that lower molecular weight (MW), labile, phytoplankton-derived compounds were degraded first, followed by petroleum-derived exogenous pollutants, and finally by higher MW polymeric plant material. This shift in utilization coincided with a community succession and increased extracellular enzyme activities. Thus, sequential utilization of different carbon pools induced changes at both the community and cellular level, shifting community composition, enzyme activity, respiration rates, and residual organic matter reactivity. Our results provide novel insight into the accessibility of sedimentary organic matter and demonstrate how bioavailability of natural organic substrates may affect the function and composition of heterotrophic bacterial populations.


Long-term results of custom cementless-stem total hip arthroplasty performed in hip fusion.
Due to complex anatomical considerations, results of cementless-stem total hip arthroplasty (THA) in hip fusion remain controversial compared with conventional THA. We therefore aimed to analyse 3D anatomy of the fused hip based on pre-operative computed tomography (CT) scans, functional outcomes based on the Harris Hip Score (HHS) and the Hip Disability and Osteoarthritis Outcome Score (HOOS), modifications of hip anatomy based on post-operative standardised radiography, and determine complication rate and long-term survival based on Kaplan-Meier analysis. We retrospectively studied 23 hips that underwent conversion of a fused hip to THA using a 3D CT scan-based custom titanium (Ti alloy hypoxyapetite (HA)-coated stem. The mean follow-up was 15 (9-22) years. Femur anteversion ranged from -29° to 80°. HHS improved from 59 to 89 points and average range of motion (ROM) was 88° for flexion. Back pain decreased in 62%, and knee pain decreased in 42%. The mean post-operative leg-length discrepancy was 7.8 mm. No intra-operative complications occurred. One aseptic stem loosening for mechanical failure was observed. The Kaplan-Meier survivorship considering revision for any reasons as the end point was 95.6% [95% confidence interval (CI) 92.4-98.8] at 15 years. Custom cementless stems may be an interesting solution to address the particular anatomical features of hip fusion at the time of THA, with an excellent survival rate at 15 years.


Intense pulsed light and laser treatment of facial telangiectasias and dyspigmentation: some theoretical and practical comparisons.
A comparative overview is presented, both theoretical and clinical, for intense pulsed light (IPL) and laser treatment of facial telangiectasias and pigmented lesions. A narrative approach describes light penetration into the epidermis, dermis, dermal-epidermal junction, and facial ectasias. Based on mathematical models, we examine some temperature profiles for monochromatic and broadband light sources. Specifically, temperature elevations of representative vascular targets are discussed. Also, clinical scenarios are reviewed for both IPL and laser. Although multiple monochromatic devices are reviewed, only the 532 and 595 nm wavelengths are emphasized. In theory, an IPL can be filtered to simulate 532 and 595 nm laser light in the treatment of telangiectasias and dyschromias. In comparing our experiences with the different devices, all three (IPL, 532 nm laser, and 595 nm laser) are capable of achieving a reduction in ectasias and hyperpigmented macules. With an optimal set of parameters, IPLs and lasers are comparable in the treatment of vascular and pigmented lesions with respect to treatment efficiency and safety.


Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans.
Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation (r2=0.29, P<0.00001). In young mice, 6 months of dietary supplementation with trimethylamine-N-oxide induced an aging-like impairment in carotid artery endothelium-dependent dilation to acetylcholine versus control feeding (peak dilation: 79±3% versus 95±3%, P<0.01). This impairment was accompanied by increased vascular nitrotyrosine, a marker of oxidative stress, and reversed by the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl. Trimethylamine-N-oxide supplementation also reduced activation of endothelial nitric oxide synthase and impaired nitric oxide-mediated dilation, as assessed with the nitric oxide synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester). Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events. Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation. Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide. Using multiple experimental approaches in mice and humans, we demonstrate a clear role of trimethylamine-N-oxide in promoting age-related endothelial dysfunction via oxidative stress, which may have implications for prevention of cardiovascular diseases.


The Association Between Duration of School Garden Exposure and Self-Reported Learning and School Connectedness.
When students feel connected to their school, they experience positive health and academic outcomes. In contrast, school disengagement is a predictor of dropout, delinquency, and substance use. School garden programming has the potential to help children achieve academic outcomes and feel connected to their school. Unfortunately, most school garden research has been conducted with white, affluent study participants. We describe the results of a secondary analysis utilizing data from an evaluation of a university-supported community school garden program (CSGP). Using a cross-sectional survey study design, we examined the impact of school garden programming in Title I schools on primarily Latino/a (Hispanic) elementary student self-reported learning and feelings of school connectedness by comparing students with ≤1 year exposure to those with >1 year. Social cognitive theory formed the conceptual basis for the analysis. Duration of school garden exposure did not have a significant association with self-reported learning or feelings of school connectedness. Regardless of past exposure, fifth-grade students, females, and those who identify as Latino/a (Hispanic) felt that school garden programming improved their learning. Latino/a (Hispanic) students who participate in school garden programming may also feel a greater sense of connection to their teachers and peers at school. Qualitative results demonstrated that most students enjoyed spending time in the garden and indicated that participating in the program helped them learn new things and feel connected to their school. If individuals who may be disadvantaged because of systemic racism, such as Latino/a (Hispanic) students, can benefit from school garden programming, such interventions should be further investigated and prioritized.


Cosyntropin as a diagnostic agent in the screening of patients for adrenocortical insufficiency.
Adrenocortical insufficiency occurs when there is inadequate release of cortisol from the adrenal cortex. Disturbances of the hypothalamic-pituitary-adrenal axis are common following trauma, surgical stress, and critical illness. While this is often a protective mechanism, these responses may become "uncoupled" or maladaptive resulting in an exacerbation of organ failure and higher mortality rates. In these clinical settings, the patient presents with a persistent systemic inflammation state, a hyperdynamic cardiovascular response, and vasopressor dependent shock. As such, the occurrence of adrenal insufficiency in the setting of critical illness is most appropriately termed critical illness-related corticosteroid insufficiency. In these settings, recent data suggests that these patients may benefit from a short course of low-dose steroid replacement therapy. Cosyntropin, a synthetic derivative of adrenocorticotropic hormone, is being used with increased frequency in the evaluation and diagnosis of adrenocortical insufficiency in this patient population. A random cortisol level is checked before a 250-μg injection of cosyntropin and then 30-60 minutes later. The cortisol levels and response to cosyntropin may be interpreted to identify an insufficient adrenal response. Of note, the setting of critical illness can greatly affect the cosyntropin test sensitivity on identifying adrenal insufficiency. Changes in the stress response during critical illness combined with the resuscitation and management of these patients greatly disturbs serum protein levels, especially those of albumin and transcortin. Common intensive care unit (ICU) diagnoses such as sepsis and malnutrition can increase baseline levels and blunt the cortisol response to cosyntropin stimulation, respectively. As well, numerous pharmacological agents routinely used in the ICU have been shown to interfere with cortisol levels and cosyntropin responsiveness. While steroids have a place in the ICU, specific dosing and length of administration remain inconsistent.


Prognosis of breast cancer and gene expression profiling using DNA arrays.
Breast cancer is a complex genetic disease characterized by the accumulation of multiple molecular alterations. The resulting clinical heterogeneity makes current therapeutic strategies-based on clinicopathlogical factors-less than perfectly adapted to each patient. Today, DNA arrays, by allowing the simultaneous and quantitative analysis of the mRNA expression levels of thousands of genes in a single assay, provide novel tools to tackle this complexity. Potential applications are multiple in the cancer field and the first research results are promising. Using home-made DNA arrays in an approach easily compatible with academic research-nylon support and radioactive detection-we identified a predictor set of 23 genes whose expression patterns differentiated two groups of breast cancer patients with different survival after adjuvant chemotherapy. We then validated and further extended these results in a larger, independent and homogeneous series of poor prognosis primary breast cancers treated with adjuvant anthracyclin-based chemotherapy. We confirmed the prognostic classification provided by the 23-gene set predictor. We then improved the predictor set and refined the classification by sorting the tumors into three classes with significantly different long-term survival. These results show the potential of the technology with an accessible approach for academic research teams. We also showed that nylon DNA arrays with radioactive detection are associated with excellent sensitivity, an advantage in clinical situations where the amount of available material is limited.


Human recombinant interferon gamma enhances neonatal polymorphonuclear leukocyte activation and movement, and increases free intracellular calcium.
In previous studies, we have reported that after chemotactic factor stimulation, PMNs from neonates fail to undergo certain critical activation steps. Furthermore, the concentration of free intracellular calcium reached is significantly below that of PMNs from adults. Interferon-gamma (IFN-gamma) is a lymphokine that has been shown to activate phagocytic cells, and IFN-gamma messenger RNA production by neonatal mononuclear leukocytes has been reported to be depressed. In the present studies, we found that recombinant human IFN-gamma markedly enhanced the chemotactic responses of PMNs from neonates to levels that were not different from that of PMNs from adults. Furthermore, preincubation of the neonatal cells with this recombinant human lymphokine also corrected the abnormality in intracellular calcium metabolism. These results suggest that this developmental defect in phagocytic cell movement may be the result of an intrinsic defect in IFN-gamma production resulting in deficiency of this critical phagocyte-activating lymphokine.


P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus.
P2Y12 receptor (P2Y12-R) signaling is mediated through Gi, ultimately reducing cellular cAMP levels. Because cAMP is a central modulator of arginine vasopressin (AVP)-induced water transport in the renal collecting duct (CD), we hypothesized that if expressed in the CD, P2Y12-R may play a role in renal handling of water in health and in nephrogenic diabetes insipidus. We found P2Y12-R mRNA expression in rat kidney, and immunolocalized its protein and aquaporin-2 (AQP2) in CD principal cells. Administration of clopidogrel bisulfate, an irreversible inhibitor of P2Y12-R, significantly increased urine concentration and AQP2 protein in the kidneys of Sprague-Dawley rats. Notably, clopidogrel did not alter urine concentration in Brattleboro rats that lack AVP. Clopidogrel administration also significantly ameliorated lithium-induced polyuria, improved urine concentrating ability and AQP2 protein abundance, and reversed the lithium-induced increase in free-water excretion, without decreasing blood or kidney tissue lithium levels. Clopidogrel administration also augmented the lithium-induced increase in urinary AVP excretion and suppressed the lithium-induced increase in urinary nitrates/nitrites (nitric oxide production) and 8-isoprostane (oxidative stress). Furthermore, selective blockade of P2Y12-R by the reversible antagonist PSB-0739 in primary cultures of rat inner medullary CD cells potentiated the expression of AQP2 and AQP3 mRNA, and cAMP production induced by dDAVP (desmopressin). In conclusion, pharmacologic blockade of renal P2Y12-R increases urinary concentrating ability by augmenting the effect of AVP on the kidney and ameliorates lithium-induced NDI by potentiating the action of AVP on the CD. This strategy may offer a novel and effective therapy for lithium-induced NDI.


Comprehensive Cross-Population Analysis of High-Grade Serous Ovarian Cancer Supports No More Than Three Subtypes.
Four gene expression subtypes of high-grade serous ovarian cancer (HGSC) have been previously described. In these early studies, a fraction of samples that did not fit well into the four subtype classifications were excluded. Therefore, we sought to systematically determine the concordance of transcriptomic HGSC subtypes across populations without removing any samples. We created a bioinformatics pipeline to independently cluster the five largest mRNA expression datasets using k-means and nonnegative matrix factorization (NMF). We summarized differential expression patterns to compare clusters across studies. While previous studies reported four subtypes, our cross-population comparison does not support four. Because these results contrast with previous reports, we attempted to reproduce analyses performed in those studies. Our results suggest that early results favoring four subtypes may have been driven by the inclusion of serous borderline tumors. In summary, our analysis suggests that either two or three, but not four, gene expression subtypes are most consistent across datasets.


A new method for RAPD primers selection based on primer bias in nucleotide sequence data.
Sequence analysis has proved that decamer nucleotides, used as primers of RAPD (random amplified polymorphic DNA), differ with each other greatly in number of annealing sites in the Arabidopsis thaliana genome. It is called the 'primer bias' by the authors. The biased primers produce a highly variable number of amplicons by polymerase chain reaction (PCR). The number of amplicons is proved to correlate with the number of annealing sites. Therefore, a statistical method is proposed for selecting efficient primers based on the primer bias in the genomic sequence. The method was tested by experiment in A. thaliana genome, and the results demonstrate that the method outperforms routine methods and can substantially increase the efficiency of RAPD methodologies. We also proved that the expressed sequence tags (ESTs) show a highly coincident bias pattern with that of the whole genomic sequence, and can therefore be used to assess efficiencies of primers for species whose genomic sequence data are currently unknown.


Detection, identification, and quantification of hydroxylated bis(2-ethylhexyl)-tetrabromophthalate isomers in house dust.
Ultra-High Resolution LC/mass spectrometry (LC-UHRMS; Thermo Fisher Q-Exactive) was used to identify two novel isomers of hydroxylated bis(2-ethylhexyl)-tetrabromophthalate (OH-TBPH) which were unexpectedly observed in a commercial standard of TBPH. By combining ultra-high resolution (UHR) mass spectra (MS(1)), mass errors to theoretical [TBPH-Br+O](-) were 2.1 and 1.0 ppm for the two isomers, UHR-MS(2) spectra and NMR analysis; the structures of the two compounds were identified as hydroxylated TBPH with a hydroxyl group on the aromatic ring. Relatively great proportions of the two isomers of OH-TBPH were detected in two technical products, Firemaster 550 (FM-550; 0.1% and 6.2%, respectively) and Firemaster BZ 54 (BZ-54; 0.1% and 7.9%), compared to a commercial standard (0.4% and 0.9%). To simultaneously analyze OH-TBPH isomers and TBPH in samples of dust, a method based on LC-UHRMS was developed to quantify the two compounds, using negative and positive ion modes, respectively. The instrumental limit of detection for TBPH was 0.01 μg/L, which was 200-300 times better than traditional methods (2.5 μg/L) based on gas chromatography-mass spectrometry. The analytical method combined with a Florisil cleanup was successfully applied to analyze TBPH and OH-TBPH in 23 indoor dust samples from Saskatoon, Saskatchewan, Canada. Two OH-TBPH isomers, OH-TBPH1 and OH-TBPH2, were detected in 52% and 91% of dust samples, respectively. Concentrations of OH-TBPH2 (0.35 ± 1.0 ng/g) were 10-fold greater than those of OH-TBPH1 (0.04 ± 0.88 ng/g) in dust, which was similar to profiles in FM-550 and BZ-54. TBPH was also detected in 100% of dust samples with a mean concentration of 733 ± 0.87 ng/g. A significant (p < 0.001) log-linear relationship was observed between TBPH and OH-TBPH isomers, further supporting the hypothesis of a common source of emission. Relatively small proportions of OH-TBPH isomers were detected in dust (0.01% ± 0.67 OH-TBPH1 and 0.1% ± 0.60 OH-TBPH2), which were significantly less than those in technical products (p < 0.001). This result indicated different environmental behaviors of OH-TBPH and TBPH. Detection of isomers of OH-TBPH is important, since compounds with phenolic groups have often shown relatively greater toxicities than nonhydroxylated analogues. Further study is warranted to clarify the environmental behaviors and potential toxicities of OH-TBPH isomers.


The small east african shorthorn zebu cows in Kenya. I: linear body measurements.
Assessment of genetic diversity is a prerequisite for the management and conservation of animal genetic resources. Appropriate design of breeding programmes is therefore impossible for breeds that have not been adequately characterized either phenotypically and/or genetically. Phenotypic characteristics are important in breed identification and classification in ways that farming communities can relate with. This study phenotypically characterized two breeds of zebu cattle in Kenya. A total of 12 measurements (face length, ear length, horn length, heart girth, height at withers, chest depth, body length, height at rump, pelvis width, corpus length, pin bone width and tail length) were collected on 373 Maasai and 277 Kamba zebu kept by traditional farmers in south-east Kenya. The data were classified on the basis of breed group, age group, sex and coat colour pattern. Breed group, age group and sex significantly influenced all measurements. Coat colour pattern significantly influenced only height at withers, corpus length, ear length and tail length. Except for horn and ear length, all the other measurements were significantly higher for the Maasai zebu. Additionally, the Maasai zebu was taller than it was long. The opposite was true for the Kamba zebu. The Maasai and Kamba zebus can be classified as medium-sized breeds; however, great variations exist in their body sizes within and between the breeds.


Treating anemia associated with chronic renal failure with erythropoiesis stimulators: recombinant human erythropoietin might be the best among the available choices.
Chronic renal failure (CRF) is a widespread medical problem commonly accompanied by a hypoproliferative anemia ("renal anemia") due to erythropoietin deficiency. Anemia greatly contributes to reduced quality of life (Hr-QoL) and high morbidity and mortality in CRF patients. Recombinant human erythropoietin (rHu-Epo) was introduced to medical practice some 20years ago. It enables correction of anemia (hemoglobin levels, Hb) with dramatic immediate (Hr-QoL improvement) and long-term effects (reduced morbidity and mortality). Newer experimental data suggest that long-term benefits could be due not only to antianemic effect, but also to a direct organoprotective effect of (rHu)-Epo mediated through a receptor complex different from the "erythropoietic" erythropoietin receptor. During the last decade, two alternative treatments for renal anemia have been approved: darbepoetin and CERA. Both are direct agonists of the "erythropoietic" receptors and both were derived from rHu-Epo. Molecularly, they differ from rHu-Epo in that they are much larger molecules (darbepoetin is genetically modified rHu-Epo with a higher sugar content and CERA is pegylated rHu-Epo) with lower affinity for the erythropoietin receptor but with a longer circulating time. In terms of renal anemia correction, they are non-inferior to rHu-Epo and allow for less frequent dosing. They have never been compared to rHu-Epo regarding the long-term outcomes. It is hypothesized that regarding the long-term outcomes (morbidity, mortality), rHu-Epo might be superior to those larger molecules. The hypothesis is based on two types of observations. First, experimental data emphasize the role of small, erythropoietically less valuable rHu-Epo isoforms in its organoprotective effects. Second, clinical observations suggest that rHu-Epo enables for less variable Hb correction than the larger molecules, and pronounced within-subject Hb variability has been suggested as an independent predictor of poor long-term outcomes of renal anemia management.


Band offsets at the Si/SiO2 interface from many-body perturbation theory.
We use many-body perturbation theory, the state-of-the-art method for band-gap calculations, to compute the band offsets at the Si/SiO2 interface. We examine the adequacy of the usual approximations in this context. We show that (i) the separate treatment of band structure and potential lineup contributions, the latter being evaluated within density-functional theory, is justified, (ii) most plasmon-pole models lead to inaccuracies in the absolute quasiparticle corrections, (iii) vertex corrections can be neglected, and (iv) eigenenergy self-consistency is adequate. Our theoretical offsets agree with the experimental ones within 0.3 eV.


Hyaluronic acid-based hydrogels crosslinked by copper-catalyzed azide-alkyne cycloaddition with tailorable mechanical properties.
Biopolymers of the extracellular matrix are attractive starting materials for providing degradable and biocompatible biomaterials. In this study, hyaluronic acid-based hydrogels with tunable mechanical properties were prepared by the use of copper- catalyzed azide-alkyne cycloaddition (known as "click chemistry"). Alkyne-functionalized hyaluronic acid was crosslinked with linkers having two terminal azide functionalities, varying crosslinker density as well as the lengths and rigidity of the linker molecules. By variation of the crosslinker density and crosslinker type, hydrogels with elastic moduli in the range of 0.5-4 kPa were prepared. The washed materials contained a maximum of 6.8 mg copper per kg dry weight and the eluate of the gel crosslinked with diazidostilbene did not show toxic effects on L929 cells. The hyaluronic acid-based hydrogels have potential as biomaterials for cell culture or soft tissue regeneration applications.


Prevention of suicidal behavior in adolescents with post-traumatic stress disorder.
Post-traumatic stress disorder (PTSD) is significantly associated with an increased risk for suicidal behavior among adolescents. Suicide is one of the top three causes of adolescent deaths worldwide. Despite the strong relationship between PTSD and suicidal behavior, precise causal pathways linking PTSD to suicide in adolescents remains unclear. A slew of mediating factors and variables commonly present themselves with both suicide and PTSD, including co-morbid psychiatric disorders, exposure to different forms of trauma and stressful life events, core neurobiological changes, and mental, emotional, and physiological states such as hyperarousal, impulsivity, and aggression. Because youth is such a critical stage of development, it is very important that at-risk adolescents are identified and referred for treatment. With many treatment challenges in these populations, effective implementation and use of prevention methods are of increasing importance. The most proven prevention methods include physician education, means restriction, and gatekeeper training. Other strategies that have received empirical support are public education campaigns and implementing guidelines for the media, including those for television, print media, and the Internet.


Methodological Variables in the Analysis of Cell-Free DNA.
In recent years, cell-free DNA (cfDNA) analysis has received increasing amounts of attention as a potential non-invasive screening tool for the early detection of genetic aberrations and a wide variety of diseases, especially cancer. However, except for some prenatal tests and BEAMing, a technique used to detect mutations in various genes of cancer patients, cfDNA analysis is not yet routinely applied in clinical practice. Although some confusing biological factors inherent to the in vivo setting play a key part, it is becoming increasingly clear that this struggle is mainly due to the lack of an analytical consensus, especially as regards quantitative analyses of cfDNA. In order to use quantitative analysis of cfDNA with confidence, process optimization and standardization are crucial. In this work we aim to elucidate the most confounding variables of each preanalytical step that must be considered for process optimization and equivalence of procedures.


The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) Observational Study.
Bladder dysfunction is a common symptom of multiple sclerosis (MS). This study was designed to evaluate effects of natalizumab on bladder function in patients with relapsing-remitting MS. The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was an open-label, single-arm, two-center study. Natalizumab-naive MS patients with disabling bladder dysfunction and initiating natalizumab were enrolled and followed for 6 months. The primary endpoint was change in the Urogenital Distress Inventory short form (UDI-6) score from baseline. Change in Incontinence Impact Questionnaire short form (IIQ-7) score from baseline was a secondary endpoint. Thirty patients were enrolled. Mean baseline characteristics were age 49.9 years, Expanded Disability Status Scale score 4.6, number of relapses in previous year 2.4, UDI-6 score 10.4, and IIQ-7 score 12.3. Mean changes in UDI-6 and IIQ-7 scores were significantly improved from baseline beginning at week 4 and up to week 24; mean improvements at 24 weeks were 4.4 (P < .0001) and 4.9 (P = .0005) points, respectively. At week 24, 85.7% and 78.6% of patients demonstrated improvements from baseline in UDI-6 and IIQ-7 scores, respectively. Incontinence-related quality of life as measured by UDI-6 and IIQ-7 scores improved significantly during natalizumab treatment.


The Healthy Activity Program (HAP), a lay counsellor-delivered brief psychological treatment for severe depression, in primary care in India: a randomised controlled trial.
Although structured psychological treatments are recommended as first-line interventions for depression, only a small fraction of people globally receive these treatments because of poor access in routine primary care. We assessed the effectiveness and cost-effectiveness of a brief psychological treatment (Healthy Activity Program [HAP]) for delivery by lay counsellors to patients with moderately severe to severe depression in primary health-care settings. In this randomised controlled trial, we recruited participants aged 18-65 years scoring more than 14 on the Patient Health Questionnaire 9 (PHQ-9) indicating moderately severe to severe depression from ten primary health centres in Goa, India. Pregnant women or patients who needed urgent medical attention or were unable to communicate clearly were not eligible. Participants were randomly allocated (1:1) to enhanced usual care (EUC) alone or EUC combined with HAP in randomly sized blocks (block size four to six [two to four for men]), stratified by primary health centre and sex, and allocation was concealed with use of sequential numbered opaque envelopes. Physicians providing EUC were masked. Primary outcomes were depression symptom severity on the Beck Depression Inventory version II and remission from depression (PHQ-9 score of <10) at 3 months in the intention-to-treat population, assessed by masked field researchers. Secondary outcomes were disability, days unable to work, behavioural activation, suicidal thoughts or attempts, intimate partner violence, and resource use and costs of illness. We assessed serious adverse events in the per-protocol population. This trial is registered with the ISRCTN registry, number ISRCTN95149997. Between Oct 28, 2013, and July 29, 2015, we enrolled and randomly allocated 495 participants (247 [50%] to the EUC plus HAP group [two of whom were subsequently excluded because of protocol violations] and 248 [50%] to the EUC alone group), of whom 466 (95%) completed the 3 month primary outcome assessment (230 [49%] in the EUC plus HAP group and 236 [51%] in the EUC alone group). Participants in the EUC plus HAP group had significantly lower symptom severity (Beck Depression Inventory version II in EUC plus HAP group 19·99 [SD 15·70] vs 27·52 [13·26] in EUC alone group; adjusted mean difference -7·57 [95% CI -10·27 to -4·86]; p<0·0001) and higher remission (147 [64%] of 230 had a PHQ-9 score of <10 in the HAP plus EUC group vs 91 [39%] of 236 in the EUC alone group; adjusted prevalence ratio 1·61 [1·34-1·93]) than did those in the EUC alone group. EUC plus HAP showed better results than did EUC alone for the secondary outcomes of disability (adjusted mean difference -2·73 [-4·39 to -1·06]; p=0·001), days out of work (-2·29 [-3·84 to -0·73]; p=0·004), intimate partner physical violence in women (0·53 [0·29-0·96]; p=0·04), behavioural activation (2·17 [1·34-3·00]; p<0·0001), and suicidal thoughts or attempts (0·61 [0·45-0·83]; p=0·001). The incremental cost per quality-adjusted life-year gained was $9333 (95% CI 3862-28 169; 2015 international dollars), with an 87% chance of being cost-effective in the study setting. Serious adverse events were infrequent and similar between groups (nine [4%] in the EUC plus HAP group vs ten [4%] in the EUC alone group; p=1·00). HAP delivered by lay counsellors plus EUC was better than EUC alone was for patients with moderately severe to severe depression in routine primary care in Goa, India. HAP was readily accepted by this previously untreated population and was cost-effective in this setting. HAP could be a key strategy to reduce the treatment gap for depressive disorders, the leading mental health disorder worldwide. Wellcome Trust.


miR-29b participates in early aneurysm development in Marfan syndrome.
Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-β (TGF-β) signaling. Although TGF-β blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-β causes aneurysms remain ill-defined. We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS. Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor κB, a repressor of miR-29b, and a factor suppressed by TGF-β, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor κB inhibitor increased miR-29b levels, whereas TGF-β blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies. We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.


Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism.
Tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. An acute increase in tumor oxygenation before radiation treatment should therefore significantly improve the tumor cell kill after radiation. Efforts to increase oxygen delivery to the tumor have not shown positive clinical results. Here we show that targeting mitochondrial respiration results in a significant reduction of the tumor cells' demand for oxygen, leading to increased tumor oxygenation and radiation response. We identified an activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. We also provide genetic evidence that papaverine's complex I inhibition is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects. Importantly, this radiosensitizing strategy will not sensitize well-oxygenated normal tissue, thereby increasing the therapeutic index of radiotherapy.


Macrophage-stimulating protein (MSP) and its receptor, RON, stimulate human osteoclast activity but not proliferation: effect of MSP distinct from that of hepatocyte growth factor.
Stem cell-derived tyrosine kinase (STK) is a member of the hepatocyte growth factor (HGF) receptor family. The ligand for STK, macrophage-stimulating protein (MSP), is a serum protein activated by members of the coagulation cascade. The RON gene is a human homolog of the murine STK. In this study we examined the role of MSP-RON in the signal pathway of human osteoclasts. Using anti-RON antibody, we detected RON expressed in multinucleated osteoclast-like cells (OCLs) formed in cultures of human bone marrow cells. To determine bone resorption, we placed OCLs on thin films of ceramic calcium phosphate formed on quartz plate-coated slides (Millenium Biologix) and measured pit formation. MSP stimulated pit formation by OCLs in a dose-dependent manner. MSP (50 ng/mL) caused a fourfold increase in pit area compared with the control. Furthermore, we examined the effects of MSP and HGF on OCL formation by purified populations of hematopoietic progenitors. OCLs were phenotypically identified by their cross-reactivity with 23c6, a monoclonal antibody that preferentially binds to osteoclasts. HGF (50 ng/mL) stimulated the differentiation of progenitors to 23c6-positive OCLs but did not enhance bone absorption. In contrast, MSP did not affect proliferation of osteoclast precursors but stimulated bone resorption by OCLs. We conclude that the MSP signal transduction pathway plays a role in bone resorption that is distinct from that of HGF.


Analysis of biotinylated generation 4 poly(amidoamine) (PAMAM) dendrimer distribution in the rat brain and toxicity in a cellular model of the blood-brain barrier.
Dendrimers are highly customizable nanopolymers with qualities that make them ideal for drug delivery. The high binding affinity of biotin/avidin provides a useful approach to fluorescently label synthesized dendrimer-conjugates in cells and tissues. In addition, biotin may facilitate delivery of dendrimers through the blood-brain barrier (BBB) via carrier-mediated endocytosis. The purpose of this research was to: (1) measure toxicity using lactate dehydrogenase (LDH) assays of generation (G)4 biotinylated and non-biotinylated poly(amidoamine) (PAMAM) dendrimers in a co-culture model of the BBB, (2) determine distribution of dendrimers in the rat brain, kidney, and liver following systemic administration of dendrimers, and (3) conduct atomic force microscopy (AFM) on rat brain sections following systemic administration of dendrimers. LDH measurements showed that biotinylated dendrimers were toxic to cell co-culture after 48 h of treatment. Distribution studies showed evidence of biotinylated and non-biotinylated PAMAM dendrimers in brain. AFM studies showed evidence of dendrimers only in brain tissue of treated rats. These results indicate that biotinylation does not decrease toxicity associated with PAMAM dendrimers and that biotinylated PAMAM dendrimers distribute in the brain. Furthermore, this article provides evidence of nanoparticles in brain tissue following systemic administration of nanoparticles supported by both fluorescence microscopy and AFM.


High frequency home-based exercise decreases levels of vascular endothelial growth factor in patients with stable angina pectoris.
In coronary artery disease (CAD), circulating angiogenic factors have been seen to increase, possibly as a response to ischaemia. Regular physical activity (PA) is recommended for prevention and treatment of CAD, but more research is needed to optimise PA regimes. We investigated the effect of home-based high frequency exercise (HFE) on angiogenic cytokines and cardiac markers in patients with stable CAD. This was a randomised case-control study Sixty-two patients, with stable CAD, were randomised to HFE (n = 33), (aerobic exercise 70% of max, 30 min, five times/week and resistance exercise three times/week), performed at home, or usual lifestyle (control, n = 29). After eight weeks, percutaneous coronary intervention (PCI) was performed in both groups, and the HFE group continued another six months of exercise. Serum vascular endothelial growth factor (VEGF) and stromal derived factor-1 (SDF-1), plasma N-terminal-brain natriuretic peptide (NT-proBNP), high-sensitive troponin T (TnT) and copeptin were analysed. Data are presented as median (25(th), 75(th) percentile) of relative changes (%) from baseline. Values of p are given for the difference between the HFE and controls. HFE decreased circulating VEGF levels, before PCI (-5% (-15%, -2%)), while VEGF levels increased in the control group (5% (-3%, 20%) p = 0.004). A significant difference in VEGF remained at three months post-PCI (HFE (-1%(-12%, 5%), control (7% (0%, 14%), p = 0.04), but not at six months after PCI. SDF-1, NT-proBNP, TnT and copeptin levels did not differ significantly. In addition, VEGF levels were positively correlated to NT pro-BNP. Home-based HFE decreased circulating VEGF in patients with stable CAD, suggesting a reduced ischaemic burden. HFE does not increase markers of cardiac dysfunction, suggesting that it is a safe therapeutic intervention in these patients.


Information theory and solar energy collection.
Information theory is applied to the problem of solar radiation collection. We find that the optimum solar concentrator corresponds to a perfect imaging system, i.e., one that images the entire sky on the absorber with no aberrations. For a nonisotropic distribution of radiation at the collector aperture, many thermally separated absorber segments are necessary at the absorber for optimum performance. The heat transfer fluid is first passed through the warm segments and then passed sequentially through the progressively hotter segments.


Bütschli dynamic droplet system.
Dynamical oil-water systems such as droplets display lifelike properties and may lend themselves to chemical programming to perform useful work, specifically with respect to the built environment. We present Bütschli water-in-oil droplets as a model for further investigation into the development of a technology with living properties. Otto Bütschli first described the system in 1898, when he used alkaline water droplets in olive oil to initiate a saponification reaction. This simple recipe produced structures that moved and exhibited characteristics that resembled, at least superficially, the amoeba. We reconstructed the Bütschli system and observed its life span under a light microscope, observing chemical patterns and droplet behaviors in nearly three hundred replicate experiments. Self-organizing patterns were observed, and during this dynamic, embodied phase the droplets provided a means of introducing temporal and spatial order in the system with the potential for chemical programmability. The authors propose that the discrete formation of dynamic droplets, characterized by their lifelike behavior patterns, during a variable window of time (from 30 s to 30 min after the addition of alkaline water to the oil phase), qualify this system as an example of living technology. The analysis of the Bütschli droplets suggests that a set of conditions may precede the emergence of lifelike characteristics and exemplifies the richness of this rudimentary chemical system, not only for artificial life investigations but also for possible real-world applications in architectural practice.


Gingival margin changes in maxillary anterior sites after single immediate implant placement and provisionalization: a 5-year retrospective study of 47 patients.
To evaluate gingival margin changes in the esthetic zone after immediate implant placement and provisionalization over 5 years with a custom anatomic provisional abutment. Single maxillary incisor immediate implant placement and provisionalization procedures, completed and followed between February 2006 and August 2006, were analyzed retrospectively. During clinical recalls at 3 months, 1 year, and 5 years, changes in gingival margins were recorded with clinical photographs and recorded in millimeters. Forty-seven patients each received a single implant (19 central incisors, 28 lateral incisors) and were followed for 5 years. Implants and restorations had a 100% survival rate during the study. The mean gingival margin changes (recession) were 0.17 mm at the time of definitive restoration, 0.27 mm at 3 months, 0.30 mm at 1 year, and 0.30 mm at 5 years. After 5 years, 24 of the 47 implant crowns had no significant gingival recession. All central incisor sites received 4.3-mm-diameter implants and had a mean change in tooth length of 0.03 mm at 5 years. Lateral incisor sites (n=28) received either a 3.5-mm-diameter implant (n=20) or a 4.3-mm-diameter implant (n=8). Lateral sites with the 3.5-mm implant had a mean change in gingival margin height of 0.08 mm of tooth length at 5 years; lateral sites with a 4.3-mm platform displayed a mean change of 0.82 mm of tooth length. This study suggests that implant diameter, gingival biotype, surgical technique, and/or the reason for tooth loss can influence the amount of gingival recession occurring over 5 years. Most recession occurred within the first 3 months, between implant placement/provisionalization and definitive restoration. The use of a customized anatomic provisional abutment can reduce the amount and frequency of recession.


The ultrastructure and histochemistry of a nematode-induced giant cell.
The development of giant cells induced by the nematode Meloidogyne in tomato roots has been followed under controlled growth conditions and the ultrastructure and histochemistry of these structures have been examined. Entry of the nematode larvae into the roots took place within 24 hours; giant cell formation started on the 4th day and involved breakdown of the cell walls accompanied by thickening of a surrounding giant cell wall and an increase in density and area of the cytoplasm. The nuclei increased in number by simultaneous mitosis throughout a single giant cell. The peak of cytoplasmic density was reached after moulting and during egg production. The rate of protein synthesis in the giant cell is correlated with the rate of growth of the nematode. The giant cell wall is a thick, irregularly surfaced structure which contains all the normal polysaccharide components of a cell wall. The cytoplasm is rich in protein and RNA and contains mitochondria, proplastids, Golgi bodies, and a dense endoplasmic reticulum. The nuclei are large and irregular in shape and contain large nucleoli and a number of Feulgen-positive bodies scattered irregularly along the nuclear envelope. The nucleolus contains RNA and fat as well as Feulgen-positive granules which are revealed after treatment with ribonuclease. It consists of a dense outer cortex surrounding a much lighter central core and is connected at times with the Feulgen-positive bodies in the nucleus. Speculation is provided on the role of these bodies in cytoplasmic protein synthesis.


Improving continuing medical education and addressing the challenge of instituting reaccreditation.
The present postgraduate education allowance structure for general practitioners is unacceptable and inadequate on a number of counts. Improvements could be made in continuing medical education by involving learners more actively, through giving them greater ownership of their continuing medical education aims and by integrating it with the current moves towards reaccreditation. Current proposals for the implementation of reaccreditation are expensive, unacceptable to many in the general practice profession, and unconnected with present continuing medical education arrangements and the existing education structure. It would be more sensitive to current attitudes, more practical, a better use of existing facilities and more logical to improve continuing medical education by linking its improvement to the evaluation of reaccreditation in as acceptable and simple a way as possible. A framework is proposed, based on an annual educational general practitioner assessment visit in which a personal learning plan is developed as a focus for an individual's continuing medical education needs.


Identification of biomarkers for esophageal squamous cell carcinoma using feature selection and decision tree methods.
Esophageal squamous cell cancer (ESCC) is one of the most common fatal human cancers. The identification of biomarkers for early detection could be a promising strategy to decrease mortality. Previous studies utilized microarray techniques to identify more than one hundred genes; however, it is desirable to identify a small set of biomarkers for clinical use. This study proposes a sequential forward feature selection algorithm to design decision tree models for discriminating ESCC from normal tissues. Two potential biomarkers of RUVBL1 and CNIH were identified and validated based on two public available microarray datasets. To test the discrimination ability of the two biomarkers, 17 pairs of expression profiles of ESCC and normal tissues from Taiwanese male patients were measured by using microarray techniques. The classification accuracies of the two biomarkers in all three datasets were higher than 90%. Interpretable decision tree models were constructed to analyze expression patterns of the two biomarkers. RUVBL1 was consistently overexpressed in all three datasets, although we found inconsistent CNIH expression possibly affected by the diverse major risk factors for ESCC across different areas.


Europe the continent with the lowest fertility.
Although fertility rates are falling in many countries, Europe is the continent with the lowest total fertility rate (TFR). This review assesses trends in fertility rates, explores possible health and social factors and reviews the impact of health and social interventions designed to increase fertility rates. Searches were done in medical and social science databases for the most recent evidence on relevant subject headings such as TFR, contraception, migration, employment policy and family benefits. Priorities, omissions and disagreements were resolved by discussion. The average TFR in Europe is down to 1.5 children per woman and the perceived ideal family size is also declining. This low fertility rate does not seem directly caused by contraception since in Northern and Western Europe the fertility decline started in the second half of the 1960s. Factors impacting on lower fertility include the instability of modern partnerships and value changes. Government support of assisted human reproduction is beneficial for families, but the effect on TFR is extremely small. Government policies that transfer cash to families for pregnancy and child support also have small effects on the TFR. Societal support for families and for couples trying to conceive improves the lives of families but makes no substantial contribution to increased fertility rates.


First Report of Cherry leaf roll virus in Hydrangea macrophylla.
Hydrangea is a popular, summer flowering, ornamental shrub that is native to south and east Asia and North and South America, which is now cultivated throughout the world. Currently, 13 viruses belonging to eight genera have been reported in Hydrangea spp. (1). In April 2011, virus-like disease symptoms, including severe leaf deformation and chlorosis, were observed on two Hydrangea macrophylla 'Sumiko' plants from Australia being held in quarantine in New Zealand. Systemic symptoms of veinal necrosis, necrotic halo spots, and severe leaf deformation were observed on Nicotiana occidentalis '37B' 7 days after inoculation with sap from the symptomatic hydrangea plants. Upon reinoculation with sap of symptomatic leaves from N. occidentalis, necrotic ringspots and tip necrosis, typical of nepovirus infection, were observed on leaves of N. tobacum and Chenopodium quinoa, respectively. Transmission electron microscopy of negatively stained sap from symptomatic leaves of N. occidentalis revealed the presence of isometric particles ~28 nm in diameter. Total nucleic acid was extracted from the symptomatic leaves of N. occidentalis with an InviMag Plant DNA Mini Kit (Invitek GmbH, Berlin, Germany) and a KingFisher mL workstation (Thermo Scientific, Waltham, MA). Reverse transcription (RT)-PCR using the reverse primer of Werner et al. (2) and a forward primer, 5'-CGGTGGAGATGCCGGTCCTA-3' (this study), specific to the 3'-untranslated region (3'-UTR) of Cherry leaf roll virus(CLRV) produced an amplicon of ~1,150 bp from N. occidentalis. A consensus sequence of 1,140 bp generated from four clones of the PCR product (GenBank Accession No. JN418885) was 99 and 98% identical at the nucleotide level to a CLRV isolate from Rumex AGBC (GenBank No. AB168099) and Chinese chives (GenBank No. AB168098), respectively. N. occidentalis also tested positive for CLRV using polyclonal antiserum in a double antibody sandwich-ELISA (BIOREBA, Reinach, Switzerland). The presence of CLRV in the original samples and N. occidentalis was confirmed by direct sequencing of the 380-bp amplicons obtained by immunocapture RT-PCR using CLRV-specific primers (2) and the same antiserum. BLASTn analysis of these amplicons (data not submitted to GenBank) also showed 99% nucleotide identity to a New Zealand isolate from a Rubus sp. (GenBank No. AJ877162). The hydrangea plants were released from quarantine because the same strain of CLRV had previously been reported in New Zealand. To our knowledge, this is the first report of CLRV in hydrangea. CLRV is a seed and pollenborne nepovirus and can be transmitted mechanically and by grafting. Since hydrangeas are mainly vegetatively propagated and are less commonly grown from seeds, the natural spread of CLRV will depend on the movement of infected propagation material. It is unknown whether this virus causes reduction in flower quality in hydrangea as reported in other hosts but any impact on flower quality may be of economic significance in commercial nurseries. References: (1) M. Caballero et al. Plant Dis. 93:891, 2009. (2) R. Werner et al. Eur. J. For. Pathol. 27:309, 1997.


Calculations of pulsatile flow through a branch: implications for the hemodynamics of atherogenesis.
Numerical simulations of pulsatile blood flow through a symmetrical branch modeling the aortic bifurcation were carried out to assess several hemodynamic theories of atherogenesis by comparing the distribution of hemodynamic variables with that of early lesions in arterial branches. Considerable spatial and temporal variations in wall shear were found when the flow was pulsatile; the highest values occurred at the convex corner on the outer wall of the branch and in the neighborhood of the flow divider tip, and the lowest shears were experienced by the outer wall of the daughter vessel a short distance distal to the corner. Transient flow reversal occurred almost everywhere in the branch, and a transient separated region was found corresponding to the low-shear region in the daughter vessel. The shear profiles and the calculated separated region were influenced to some degree by the extent of flow development at the branch inlet and markedly by the branch area ratio. All of the proposed hemodynamic promoters of atherosclerosis that were examined--high shear, low shear, and separation--were found at sites in the branch where lesions commonly develop. Comparisons with a steady-flow calculation at the same mean flow rate showed that the severity of all of these proposed hemodynamic determinants was increased by pulsatility.


World Federation for Medical Education Policy on international recognition of medical schools' programme.
The increasing globalisation of medicine, as manifested in the migration rate of medical doctors and in the growth of cross-border education providers, has inflicted a wave of quality assurance efforts in medical education, and underlined the need for definition of standards and for introduction of effective and transparent accreditation systems. In 2004, reflecting the importance of the interface between medical education and the healthcare delivery sector, a World Health Organization (WHO)/World Federation for Medical Education (WFME) Strategic Partnership to improve medical education was formed. In 2005, the partnership published Guidelines for Accreditation of Basic Medical Education. The WHO/WFME Guidelines recommend the establishment of proper accreditation systems that are effective, independent, transparent and based on medical education-specific criteria. An important prerequisite for this development was the WFME Global Standards programme, initiated in 1997 and widely endorsed. The standards are now being used in all 6 WHO/WFME regions as a basis for quality improvement of medical education throughout its continuum and as a template for national and regional accreditation standards. Promotion of national accreditation systems will have a pivotal influence on future international appraisal of medical education. Information about accreditation status - the agencies involved and the criteria and procedure used - will be an essential component of new Global Directories of Health Professions Educational Institutions. According to an agreement between the WHO and the University of Copenhagen (UC), these Directories (the Avicenna Directories) will be developed and published by the UC with the assistance of the WFME, starting with renewal of the WHO World Directory of Medical Schools, and sequentially expanding to cover educational institutions for other health professions. The Directories will be a foundation for international meta-recognition ("accrediting the accreditors") of educational institutions and their programmes.


The Association of Fatty Acid Levels and Gleason Grade among Men Undergoing Radical Prostatectomy.
Epidemiological data suggest that omega-6 (ω-6) fatty acids (FAs) may be associated with cancer incidence and/or cancer mortality, whereas ω-3 FAs are potentially protective. We examined the association of the ratio of ω-6 to ω-3 FA (ω-6:ω-3) and individual FA components with pathological results among men with prostate cancer (PCa) undergoing radical prostatectomy. Sixty-nine men were included in the study. Components of ω-6 (linoleic acid (LA), arachidonic acid (AA), and dihomo-γ-linolenic acid (DGLA)) and ω-3 (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) were analyzed by liquid chromatography/mass selective detector separation. Logistic regression analysis was performed to determine association of FA with pathological high grade (Gleason ≥4+3) disease. The were 35 men with low grade disease (Gleason ≤3+4) and 34 men with high grade disease. Men with low grade disease were significantly younger (58y vs 61y, p = 0.012) and had lower D'Amico clinical classification (p = 0.001) compared to men with high grade disease. There was no significant association of ω-6:ω-3 with high grade disease (OR 0.93, p = 0.78), however overall ω-6, ω-3, and individual components of ω-6 and ω-3 FAs except EPA were significantly associated with high grade disease (ω-6: OR 3.37, 95% CI: 1.27,8.98; LA: OR 3.33, 95% CI:1.24,8.94; AA: OR 2.93, 95% CI:1.24,6.94; DGLA: OR 3.21, 95% CI:1.28,8.04; ω-3: OR 3.47, 95% CI:1.22,9.83; DHA: OR 3.13, 95% CI:1.26,7.74). ω-6 and ω-3 FA components were highly correlated (Spearman ρ = 0.77). Higher levels of individual components of ω-6 and ω-3FAs may be associated with higher-grade PCa. Studies into the causative factors/pathways regarding FAs and prostate carcinogenesis may prove a potential association with PCa aggressiveness.


Localized cdc42 activation, detected using a novel assay, mediates microtubule organizing center positioning in endothelial cells in response to fluid shear stress.
Fluid flow regulates morphology, physiology, and pathophysiology of vascular endothelial cells (reviewed in Ref. 1). The small GTPase Cdc42 mediates polarity in several systems including migrating cells and early embryos, which involve reorientation of the microtubule organizing center (MTOC) and Golgi apparatus toward the direction of movement. Here, we show that Cdc42 is activated by fluid shear stress and that activation is a consequence of integrins binding to extracellular matrix. A novel fluorescence energy transfer assay to visualize Cdc42 activation in single cells shows that Cdc42 activity is polarized in the direction of flow. Localized activation of Cdc42 as well as the activity of Par6 and protein kinase Czeta direct the reorientation of the MTOC to a position on the downstream side of the nucleus relative to the direction of flow. Thus, shear-stimulated integrin dynamics induce polarized Cdc42 activity, which induces MTOC localization through the Par6-protein kinase Czeta complex.


The anatomy of teleneurosurgery in china.
With its huge population and vast territory, China faces a great challenge in providing modern advanced health care services to all parts of the country. The advances of information communication technologies (ICTs) and the advent of internet have revolutionised the means in the delivery of healthcare via telemedicine to remote and underserved populations, which to a certain extent has been very well exploited in China, especially where 70% peasants residing in the rural areas. This paper reviews the latest development in telemedicine infrastructure in China with the focus on the development of teleneurosurgery, drawing from the results gained from a 3-year networking project between Europe and China on telemedicine (TIME, 2005-2007) funded by European Commission under Asia ICT programme, with an aim to shape up envisages of future medical care in China. Comparison with its counterparts in Europe is also addressed.


In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches.
This article is part of a series of reports from the "Orlando Inhalation Conference-Approaches in International Regulation" which was held in March 2014, and coorganized by the University of Florida and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of the conference was to foster the exchange of ideas and knowledge across the global scientific and regulatory community in order to identify and help move towards strategies for internationally harmonized, science-based regulatory approaches for the development and marketing approval of inhalation medicines, including innovator and second entry products. This article provides an integrated perspective of case studies and discussion related to in vitro testing of orally inhaled products, including in vitro-in vivo correlations and requirements for in vitro data and statistical analysis that support quality or bioequivalence for regulatory applications.


Ophthalmologic complications after intraoral local anesthesia.
The first ophthalmologic complication in conjunction with a dental anesthesia was reported in 1936. The objective of the present study was a detailed analysis of case reports about that topic. After conducting a literature search in PubMed this study analyzed 108 ophthalmologic complications following intraoral local anesthesia in 65 case reports with respect to patient-, anesthesia-, and complication- related factors. The mean age of the patients was 33.8 years and females predominated (72.3%). The most commonly reported complication was diplopia (39.8%), mostly resulting from paralysis of the lateral rectus muscle. Other relatively frequent complications included ptosis (16.7%), mydriasis (14.8%) and amaurosis (13%). Ophthalmologic complications were mainly associated with block anesthesia of the inferior alveolar nerve (45.8%) or the posterior superior alveolar nerve (40.3%). Typically, the ophthalmologic complications in conjunction with intraoral local anesthesia had an immediate to short onset, and disappeared as the anesthesia subsided. The increased number of ophthalmologic complications after intraoral local anesthesia in females may suggest a gender effect. Double vision (diplopia) is the most frequently described complication, which is usually completely reversible like the other reported ophthalmologic complications.


A microfibril assembly assay identifies different mechanisms of dominance underlying Marfan syndrome, stiff skin syndrome and acromelic dysplasias.
Fibrillin-1 is the major component of the 10-12 nm diameter extracellular matrix microfibrils. The majority of mutations affecting the human fibrillin-1 gene, FBN1, result in Marfan syndrome (MFS), a common connective tissue disorder characterised by tall stature, ocular and cardiovascular defects. Recently, stiff skin syndrome (SSS) and a group of syndromes known collectively as the acromelic dysplasias, which typically result in short stature, skin thickening and joint stiffness, have been linked to FBN1 mutations that affect specific domains of the fibrillin-1 protein. Despite their apparent phenotypic differences, dysregulation of transforming growth factor β (TGFβ) is a common factor in all of these disorders. Using a newly developed assay to track the secretion and incorporation of full-length, GFP-tagged fibrillin-1 into the extracellular matrix, we investigated whether or not there were differences in the secretion and microfibril assembly profiles of fibrillin-1 variants containing substitutions associated with MFS, SSS or the acromelic dysplasias. We show that substitutions in fibrillin-1 domains TB4 and TB5 that cause SSS and the acromelic dysplasias do not prevent fibrillin-1 from being secreted or assembled into microfibrils, whereas MFS-associated substitutions in these domains result in a loss of recombinant protein in the culture medium and no association with microfibrils. These results suggest fundamental differences in the dominant pathogenic mechanisms underlying MFS, SSS and the acromelic dysplasias, which give rise to TGFβ dysregulation associated with these diseases.


Effect of gestational age on screening for neural-tube defects by maternal plasma-A.F.P. measurement.
Maternal plasma or serum alpha-feto-protein (A.F.P.) concentrations were measured once between 8 and 22 weeks of gestation in each of sixty-two pregnancies which resulted in an infant with a neural-tube defect. Between 13 and 22 weeks of pregnancy twenty-two of the forty-one cases tested (54%) had A.F.P. values greater than three times the median value for unaffected pregnancies (which is equivalent to the 97th percentile of normal), and many of these values were very high indeed. However, before the 13th week of pregnancy only one of the twenty-one cases (5%) had an A.F.P. value more than three times the median for unaffected pregnancies, and this value was not very high. This indicates that in antenatal screening for anencephaly or spina bifida, A.F.P. should be measured in blood taken from the mother during the second trimester.