[Mechanisms of early light and dark adaptation].
A possible role of transient and sustained mechanisms of vision in early light and dark adaptation was studied using the adaptive fields with different rates of luminance changes. The curve forms of early light and dark adaptation and time integration at different rates of switching on and off the adaptive field were studied as well as the changes of contrast sensitivity related to rates of background luminance changes. The data obtained confirm participation of transient and sustained mechanisms of vision in early light and dark adaptation. The contribution of each mechanism depends on the rate and direction of the luminance changes.


Pathway discovery using transcriptomic profiles in adult-onset severe asthma.
Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous samples. We sought to identify gene profiles associated with adult-onset severe asthma. This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age ≥18 years) as compared with childhood-onset severe asthma (<18 years) were selected from the U-BIOPRED cohort. Gene expression was assessed on the total RNA of induced sputum (n = 83), nasal brushings (n = 41), and endobronchial brushings (n = 65) and biopsies (n = 47) (Affymetrix HT HG-U133+ PM). Gene set variation analysis was used to identify differentially enriched predefined gene signatures of leukocyte lineage, inflammatory and induced lung injury pathways. Significant differentially enriched gene signatures in patients with adult-onset as compared with childhood-onset severe asthma were identified in nasal brushings (5 signatures), sputum (3 signatures), and endobronchial brushings (6 signatures). Signatures associated with eosinophilic airway inflammation, mast cells, and group 3 innate lymphoid cells were more enriched in adult-onset severe asthma, whereas signatures associated with induced lung injury were less enriched in adult-onset severe asthma. Adult-onset severe asthma is characterized by inflammatory pathways involving eosinophils, mast cells, and group 3 innate lymphoid cells. These pathways could represent useful targets for the treatment of adult-onset severe asthma.


The Nature, Value, and Experience of Engagement in Pediatric Rehabilitation: Perspectives of Youth, Caregivers, and Service Providers.
Purpose: To conduct a qualitative investigation of engagement in pediatric rehabilitation therapy.Methods: Interviews were conducted with 10 youth, 10 caregivers, and 10 service providers. Transcripts were analyzed thematically using an inductive approach.Results: Themes illustrated three perspectives: engagement as a connection with components of the therapy process, engagement as working together, and engagement as an affective and motivational process. Engagement created valued connections with therapy components and forward momentum for therapy.Conclusions: The themes supported a view of engagement as complex, transactional, and multidimensional. Participants focused on different, yet not discrepant, aspects of engagement. Youth focused on having fun and personal connection with service providers. Caregivers provided a more complex perspective encompassing both their own and their child's engagement, with an emphasis on relationship, understanding what is taking place, and feeling valued in the process. Service providers highlighted goal attainment and the value of engagement in bringing about outcomes.


Effects of Bifidobacterium longum Subsp. infantis CECT 7210 and Lactobacillus rhamnosus HN001, Combined or Not With Oligofructose-Enriched Inulin, on Weaned Pigs Orally Challenged With Salmonella Typhimurium.
Salmonella is a common causative agent of enteric disease and is developing mechanisms of resistance to antimicrobials. Probiotics, such as bifidobacteria and lactobacilli, and prebiotic fibers are a potential alternative to counteract this pathogen as they have demonstrated effectiveness in preventing its adhesion, reducing intestinal damage, and enhancing the host immune system. Furthermore, the benefits are expected to be potentiated when these compounds are administered together. A trial was performed to evaluate the efficacy of two probiotic strains (Bifidobacterium longum subsp. infantis CECT 7210 (Laboratorios Ordesa S.L.) and Lactobacillus rhamnosus HN001, combined or not with a prebiotic containing oligofructose-enriched inulin, against Salmonella Typhimurium. Ninety-six piglets (28 days old) were distributed into 32 pens assigned to 5 treatments: one non-challenged (control diet, CTR+) and four challenged: control diet (CTR-) or supplemented with probiotics (>3 × 1010 cfu/kg each strain, PRO), prebiotic (5%, PRE), or their combination (SYN). After 1 week of adaptation, animals were orally challenged with Salmonella Typhimurium. Feed intake, weight, and clinical signs were recorded. On days 4 and 8 post-inoculation (PI), one animal per pen was euthanized, and samples from blood, digestive content, and ileal tissues were collected to determine Salmonella counts, fermentation products, ileal histomorphology, and serum TNF-α and Pig-MAP concentrations. The effect of the oral challenge was evidenced by animal performance, fecal consistency, and intestinal architecture. Regarding the experimental treatments, animals belonging to the PRO group experienced a faster clearance of the pathogen, with more pigs being negative to its excretion at the end of the study and recovering the impaired ileal villi/crypt ratio more rapidly. Animals receiving the PRE diet showed a lower intestinal colonization by Salmonella, with no countable levels (<3 cfu/g) in any of the analyzed samples, and an augmented immune response suggested by serum Pig-MAP concentrations. Treatments including the prebiotic (PRE and SYN) showed similar changes in the fermentation pattern, with an increase in the molar percentage of valeric acid concentration in the colon. The SYN group, however, did not show any of the outcomes registered for PRO and PRE in Salmonella colonization or in immunity markers, suggesting the lack of synbiotic action in this animal model. Further research is needed to better understand the complex mechanisms behind these effects.


Identification and Functional Validation of Differentially Expressed microRNAs in Ascites-Derived Ovarian Cancer Cells Compared with Primary Tumour Tissue.
Ovarian cancer, manifested by malignant ascites, is the most lethal gynaecological cancer. Suspended ascites-derived spheroids may contribute to ovarian cancer metastasis. MicroRNAs (miRNAs) are also associated with ovarian cancer metastasis. Here, we aimed to investigate the differentially expressed miRNAs (DE-miRNAs) in ascites-derived spheroids compared with primary tumour tissues, which may regulate ovarian cancer metastasis. The DE-miRNAs between ovarian cancer primary tumour tissues and ascites-derived spheroids were identified by GEO2R screening in samples from 3 high-grade serous ovarian cancer (HGSOC) patients of dataset GSE65819. We used MiRTarBase, TargetScanHuman7.2 and STRING to predict the target hub genes of DE-miRNAs and DAVID to perform functional analysis of hub genes. ALGGEN PROMO and TransmiR v2.0 were used to predict transcription factors (TFs) that potentially regulate DE-miRNAs expression. The observed differences in DE-miRNAs expression were validated with samples from 12 HGSOC patients and 2 ovarian cancer cell lines using PCR. The functions of DE-miRNAs on ovarian cancer progression were verified by invasion, adherent, and angiogenesis assays. Through bioinformatics screening and experimental validation, miR-199a-3p, miR-199b-3p, miR-199a-5p, miR-126-3p and miR-145-5p were identified as being significantly downregulated in ascites-derived spheroids compared with primary tumour tissues. In addition, TFAP2A was identified as a potentially common upstream TF regulating the expression of the above mentioned DE-miRNAs. The overexpression of miR-199a-3p, miR-199b-3p, miR-199a-5p lead to invasion inhibition, and the overexpression of miR-126-3p, miR-145-5p, miR-199a-5p and miR-199b-3p lead to adhesion inhibition of suspended ovarian cancer cells. High-expressed miR-126-3p, miR-199a-3p, miR-199a-5p and miR-199b-3p contributed to apoptosis of suspended ovarian cancer cells. The downregulated expression of miR-199a-3p, miR-199b-3p, miR-199a-5p, miR-126-3p and miR-145-5p in ascites-derived spheroids plays a key role in promoting ovarian cancer progression, which may represent novel molecules for targeted therapy for ovarian cancer.


Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer.
Skin toxicity is a known clinical signature used to predict the prognosis of anti-epidermal growth factor receptor (EGFR) antibody treatment in metastatic colorectal cancer (mCRC). There are no biological markers to predict skin toxicity before anti-EGFR antibody treatment in mCRC patients. Between August 2008 and August 2011, pretreatment serum samples were obtained from KRAS wild-type (WT) patients who received anti-EGFR antibody treatment. Serum levels of ligands were measured by ELISA. A total of 103 KRAS WT patients were enrolled in the study. Progression-free survival and overall survival of patients with a high grade (grade 2-3) of skin toxicity were significantly longer than those with a low grade (grade 0-1) of skin toxicity (median progression-free survival, 6.4 months vs 2.4 months, P < 0.001; median overall survival, 14.6 months vs 7.1 months, P = 0.006). There were significant differences in distribution of serum levels of epiregulin (EREG), amphiregulin (AREG), and hepatocyte growth factor (HGF) between groups of low/high grade of skin toxicity (P < 0.048, P < 0.012, P < 0.012, respectively). In addition, serum levels of HGF, EREG, and AREG were inversely proportional to grades of skin toxicity as determined by the Cochran-Armitage test (P = 0.019, P = 0.047, P = 0.021, respectively). Our study indicated that serum levels such as HGF, EREG, and AREG may be significant markers to predict the grade of skin toxicity and the prognosis of anti-EGFR antibody treatment, which contribute to improvement of the management of skin toxicity and survival time in mCRC patients.


A PI3K/AKT Scaffolding Protein, IQ Motif-Containing GTPase Associating Protein 1 (IQGAP1), Promotes Head and Neck Carcinogenesis.
Head and neck cancer (HNC) is the sixth most common cancer worldwide with a 5-year survival rate of less than 50%. The PI3K/AKT/mTOR signaling pathway is frequently implicated in HNC. Recently, IQ motif-containing GTPase-activating protein 1 (IQGAP1) was discovered to scaffold the PI3K/AKT signaling pathway. IQGAP1 gene expression is increased in HNC, raising the hypothesis that IQGAP1 contributes to HNC. We performed a combination of in vitro studies using human cancer cell lines treated with a cell-permeable peptide that interferes with IQGAP1's ability to bind to PI3K, and in vivo studies utilizing mice genetically knocked out for the Iqgap1 (Iqgap1 -/-). In vivo EGF stimulation assays were used to evaluate PI3K signaling. To study the role of IQGAP1 in HNC, we used a well-validated mouse model that drives HNC via a synthetic oral carcinogen, 4-nitroquinoline 1-oxide (4NQO). IQGAP1 is necessary for efficient PI3K signaling in vitro and in vivo. Disruption of IQGAP1-scaffolded PI3K/AKT signaling reduced HNC cell survival. Iqgap1 -/- mice had significantly lower cancer incidences, lesser disease severity, and fewer cancer foci. IQGAP1 protein levels were increased in HNC arising in Iqgap1+/+ mice. The level of PI3K signaling in 4NQO-induced HNC arising in Iqgap1 -/- mice was significantly reduced, consistent with the hypothesis that IQGAP1 contributes to HNC at least partly through PI3K signaling. High IQGAP1 expression correlated with reduced survival, and high pS6 levels correlated with high IQGAP1 levels in patients with HNC. These data demonstrate that IQGAP1 contributes to head and neck carcinogenesis.


Invasive Pulmonary Aspergillosis in Nonimmunocompromised Hosts.
Invasive pulmonary aspergillosis (IPA) is a fungal infection that is the hallmark of severe cellular or complex immune alterations. Evidence that IPA can occur in nonimmunocompromised hosts is increasing. Actually, up to 1% of general intensive care unit (ICU) patients present positive samples with Aspergillus spp. Both colonization and invasive disease are associated with poor outcome. Unexpected IPA has also been reported in approximately 1% of critically ill patients who underwent postmortem biopsies. In nonimmunocompromised patients with acute respiratory distress syndrome (ARDS), IPA prevalence can reach up to 15% of patients in both clinical and autopsy studies. Factors associated with IPA in nonimmunocompromised critically ill hosts include short and long courses of steroids, broad antibiotic therapy, chronic obstructive pulmonary disease, ARDS, liver failure, and the severity of organ dysfunctions.This review aims to appraise the prevalence of IPA in nonimmunocompromised hosts, address diagnostic challenges, and outcomes.


Disentangling the Role of Climate, Topography and Vegetation in Species Richness Gradients.
Environmental gradients (EG) related to climate, topography and vegetation are among the most important drivers of broad scale patterns of species richness. However, these different EG do not necessarily drive species richness in similar ways, potentially presenting synergistic associations when driving species richness. Understanding the synergism among EG allows us to address key questions arising from the effects of global climate and land use changes on biodiversity. Herein, we use variation partitioning (also know as commonality analysis) to disentangle unique and shared contributions of different EG in explaining species richness of Neotropical vertebrates. We use three broad sets of predictors to represent the environmental variability in (i) climate (annual mean temperature, temperature annual range, annual precipitation and precipitation range), (ii) topography (mean elevation, range and coefficient of variation of elevation), and (iii) vegetation (land cover diversity, standard deviation and range of forest canopy height). The shared contribution between two types of EG is used to quantify synergistic processes operating among EG, offering new perspectives on the causal relationships driving species richness. To account for spatially structured processes, we use Spatial EigenVector Mapping models. We perform analyses across groups with distinct dispersal abilities (amphibians, non-volant mammals, bats and birds) and discuss the influence of vagility on the partitioning results. Our findings indicate that broad scale patterns of vertebrate richness are mainly affected by the synergism between climate and vegetation, followed by the unique contribution of climate. Climatic factors were relatively more important in explaining species richness of good dispersers. Most of the variation in vegetation that explains vertebrate richness is climatically structured, supporting the productivity hypothesis. Further, the weak synergism between topography and vegetation urges caution when using topographic complexity as a surrogate of habitat (vegetation) heterogeneity.


Appetitive traits associated with higher and lower body mass index: evaluating the validity of the adult eating behaviour questionnaire in an Australian sample.
The aims of this study were to evaluate the factor structure of the newly developed Adult Eating Behaviour Questionnaire (AEBQ) (Hunot et al., Appetite 105:356-63, 2016) in an Australian sample, and examine associations between the four food approach and four food avoidance appetitive traits with body mass index (BMI). Participants (N = 998) recruited between May and October 2016 via a university research participation scheme and online social network sites completed an online version of the AEBQ and self-reported demographic and anthropometric data. Of the sample, 84.8% were females, 29.6% had completed a university degree and the overall mean age was 24.32 years (SD = 8.32). Confirmatory factor analysis (CFA) was used to test three alternative factor structures (derived from issues raised in the original development study): the original 8 factor model, a 7 factor model with Food Responsiveness and Hunger scales combined, and a 7 factor model with the Hunger scale removed. The CFA revealed that the original 8 factor model was a better fit to the data than the 7 factor model in which Food Responsiveness and Hunger scales were combined. However, while reliability estimates for 7 of the 8 scales were good (Cronbach's α between 0.70-0.86), the reliability of the Hunger scale was modest (0.67) and dropping this factor resulted in a good fitting model. All food avoidance scales (except Food Fussiness) were negatively associated with body mass index (BMI) whereas Emotional Overeating was the only food approach scale positively associated with BMI. The study supports the use of the AEBQ as a reliable and valid measure of food approach and avoidance appetitive traits in adults. Longitudinal studies that examine continuity and stability of appetitive traits across the lifespan will be facilitated by the addition of this measurement tool to the literature.


Observations on the life cycle and prevalence of Eimeria leuckarti in horses in Montana.
Of 22 foals from 4 localities in southwestern Montana, 59% were found to be infected with Eimeria leuckarti. Oocysts collected from feces of 4 positive horses were sporulated and subsequently administered to a 5- to 6-month-old foal. The prepatent period was 31 days and the patent period was between 5 and 10 days.


The geography and ecology of plant speciation: range overlap and niche divergence in sister species.
A goal of evolutionary biology is to understand the roles of geography and ecology in speciation. The recent shared ancestry of sister species can leave a major imprint on their geographical and ecological attributes, possibly revealing processes involved in speciation. We examined how ecological similarity, range overlap and range asymmetry are related to time since divergence of 71 sister species pairs in the California Floristic Province (CFP). We found that plants exhibit strikingly different age-range correlation patterns from those found for animals; the latter broadly support allopatric speciation as the primary mode of speciation. By contrast, plant sisters in the CFP were sympatric in 80% of cases and range sizes of sisters differed by a mean of 10-fold. Range overlap and range asymmetry were greatest in younger sisters. These results suggest that speciation mechanisms broadly grouped under 'budding' speciation, in which a larger ranged progenitor gives rise to a smaller ranged derivative species, are probably common. The ecological and reproductive similarity of sisters was significantly greater than that of sister-non-sister congeners for every trait assessed. However, shifts in at least one trait were present in 93% of the sister pairs; habitat and soil shifts were especially common. Ecological divergence did not increase with range overlap contrary to expectations under character displacement in sympatry. Our results suggest that vicariant speciation is more ubiquitous in animals than plants, perhaps owing to the sensitivity of plants to fine-scale environmental heterogeneity. Despite high levels of range overlap, ecological shifts in the process of budding speciation may result in low rates of fine-scale spatial co-occurrence. These results have implications for ecological studies of trait evolution and community assembly; despite high levels of sympatry, sister taxa and potentially other close relatives, may be missing from local communities.


Efficacy and Safety of Alogliptin in Elderly Patients With Type 2 Diabetes Mellitus.
In Japan, with increasing age of the population, diabetic patients often become in need of hemodialysis due to diabetic nephropathy, and thus there is a demand for development of diabetic treatments that take into account renal effects in the elderly. No previous studies of alogliptin had focused on Japanese elderly subjects; we therefore assessed the effects of alogliptin in elderly individuals using available data. Laboratory data were compiled for 1 year at intervals of 3 months following the start of alogliptin treatment. The subjects were divided into three groups by age: < 65 years (n = 110), 65 - 74 years (n = 87), and ≥ 75 years (n = 93). Laboratory values in comparison with baseline were compared within groups at various time points, and changes from baseline were compared among the different groups. Hemoglobin A1c (HbA1c) levels decreased significantly from baseline values in all groups at and after month 3: the change at month 12 was -0.74±1.45% for the age group < 65, -0.47±1.02% for the age group 65 - 74, and -0.42±1.11% for the age group ≥ 75. The 12-month change in estimated glomerular filtration rate (eGFR) was -6.5 ± 12.0 for the age group < 65, -2.0 ± 8.4 for the age group 65 - 74, and -1.5 ± 10.0 for the age group ≥ 75; the reduction in the age group < 65 was significant, whereas the reduction in the age groups ≥ 65 was not. Alogliptin significantly lowers HbA1c levels in the elderly and can be used without posing any safety issues, including renal effects, thus contributing to safe blood glucose control in clinical practice.


Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria.
An open, randomized comparison of artemether-benflumetol (CGP 56 697; Novartis) with artesunate-mefloquine was conducted in 617 patients with acute uncomplicated multidrug-resistant falciparum malaria on the western border of Thailand. Both treatments rapidly and reliably cleared fever and parasitemia, and there was no significant difference in the initial therapeutic response parameters. Parasite genotyping was used to distinguish recrudescences from new infections. The 63-day cure rate for artesunate-mefloquine (94%) was significantly higher than the cure rate for artemether-benflumetol (81%) (P < 0.001). Both regimens were well tolerated. Nausea, vomiting, dizziness, sleep disorders, and other neurological side effects were between two and four times more common in the artesunate-mefloquine group than in the artemether-benflumetol group (P < 0.001). Artemether-benflumetol is effective and very well tolerated in the treatment of multidrug-resistant falciparum malaria. A higher dose than that used in the present study may improve efficacy.


Risk Prediction for Prostate Cancer Recurrence Through Regularized Estimation with Simultaneous Adjustment for Nonlinear Clinical Effects.
In biomedical studies, it is of substantial interest to develop risk prediction scores using high-dimensional data such as gene expression data for clinical endpoints that are subject to censoring. In the presence of well-established clinical risk factors, investigators often prefer a procedure that also adjusts for these clinical variables. While accelerated failure time (AFT) models are a useful tool for the analysis of censored outcome data, it assumes that covariate effects on the logarithm of time-to-event are linear, which is often unrealistic in practice. We propose to build risk prediction scores through regularized rank estimation in partly linear AFT models, where high-dimensional data such as gene expression data are modeled linearly and important clinical variables are modeled nonlinearly using penalized regression splines. We show through simulation studies that our model has better operating characteristics compared to several existing models. In particular, we show that there is a non-negligible effect on prediction as well as feature selection when nonlinear clinical effects are misspecified as linear. This work is motivated by a recent prostate cancer study, where investigators collected gene expression data along with established prognostic clinical variables and the primary endpoint is time to prostate cancer recurrence. We analyzed the prostate cancer data and evaluated prediction performance of several models based on the extended c statistic for censored data, showing that 1) the relationship between the clinical variable, prostate specific antigen, and the prostate cancer recurrence is likely nonlinear, i.e., the time to recurrence decreases as PSA increases and it starts to level off when PSA becomes greater than 11; 2) correct specification of this nonlinear effect improves performance in prediction and feature selection; and 3) addition of gene expression data does not seem to further improve the performance of the resultant risk prediction scores.


Local neighbourhood and mental health: evidence from the UK.
This paper examines the association between neighbourhood and levels and changes in common mental disorders. Using data from a large scale nationally representative survey of individuals and households (the British Household Panel Survey), it locates individuals in their local neighbourhoods. These are defined as the nearest 500-800 persons centered around each individual in the survey. These 'bespoke' neighbourhoods are characterised according to five dimensions--disadvantage, mobility, age, ethnicity and urbanness--derived from factor analysis of the census characteristics of the residents of neighbourhoods in 1991. These dimensions measure characteristics of place that have been argued to be associated with mental ill health. The paper estimates multilevel models of the level and 5-year changes of common mental disorders (measured by the twelve item version of the General Health Questionnaire). Three and two level models are estimated, all of which allow for individual and household characteristics that may act as confounders of any neighbourhood effect. The results show the extent of association between neighbourhood and both levels and changes in mental health is limited. Less than one percent of the variance across individuals is at the neighbourhood level. The neighbourhood characteristics are not generally statistically associated with levels or changes in mental ill health. There is some evidence of interaction between neighbourhood characteristics and gender and ethnicity, but while statistically significant these interactions are small in size compared to the main effects of individual and household characteristics. What appears to be important for levels of common mental disorders are the observed characteristics of individuals and their households, not of place.


Pediatric restraint use is associated with reduced transports by emergency medical services providers after motor vehicle crashes.
To determine the association between pediatric restraint use during motor vehicle crashes and patient transports by emergency medical services (EMS) providers. Children under 16 years of age who were involved in motor vehicle crashes in Houston or Harris County, Texas, in 1997 were identified from Texas Department of Public Safety (DPS) crash data. DPS data were linked probabilistically to City of Houston Fire Department EMS data to identify whether the children were transported from the scene by EMS. Odds ratios were calculated to determine the association between restraint use and EMS transport. Logistic regression was used to control for age and injury severity in this relationship. From the linked data for 1997, 1,696 children were involved in reported automobile or truck crashes to which EMS responded. Of the 1,580 children about whom information concerning restraint use was available, 1,309 (83%) were wearing some type of safety restraint and 1,342 (85%) were transported by EMS. Adjusting for injury severity, children wearing safety restraints during motor vehicle crashes were 60% (95% confidence interval 34-75%) less likely to be transported by EMS than those not wearing safety restraints during such crashes. The use of safety restraints during motor vehicle crashes is associated with a reduction in the number of children transported from the scene by EMS providers. This effect is independent of age and injury severity.


Synthesis and Optimization of Mesoporous Silica Nanoparticles for Ruthenium Polypyridyl Drug Delivery.
The ruthenium polypyridyl complex [Ru(dppz)2PIP]2+ (dppz: dipyridophenazine, PIP: (2-(phenyl)-imidazo[4,5-f ][1,10]phenanthroline), or Ru-PIP, is a potential anticancer drug that acts by inhibiting DNA replication. Due to the poor dissolution of Ru-PIP in aqueous media, a drug delivery agent would be a useful approach to overcome its limited bioavailability. Mesoporous silica nanoparticles (MSNs) were synthesized via a co-condensation method by using a phenanthrolinium salt with a 16 carbon length chain (Phen-C16) as the template. Optimization of the synthesis conditions by Box-Behnken design (BBD) generated MSNs with high surface area response at 833.9 m2g-1. Ru-PIP was effectively entrapped in MSNs at 18.84%. Drug release profile analysis showed that Ru-PIP is gradually released, with a cumulative release percentage of approximately 50% at 72 h. The release kinetic profile implied that Ru-PIP was released from MSN by diffusion. The in vitro cytotoxicity of Ru-PIP, both free and MSN-encapsulated, was studied in Hela, A549, and T24 cancer cell lines. While treatment of Ru-PIP alone is moderately cytotoxic, encapsulated Ru-PIP exerted significant cytotoxicity upon all the cell lines, with half maximal inhibitory concentration (IC50) values determined by MTT (([3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyltetrazolium bromide]) assay at 48 h exposure substantially decreasing from >30 µM to <10 µM as a result of MSN encapsulation. The mechanistic potential of cytotoxicity on cell cycle distribution showed an increase in G1/S phase populations in all three cell lines. The findings indicate that MSN is an ideal drug delivery agent, as it is able to sustainably release Ru-PIP by diffusion in a prolonged treatment period.


Alpha 4 beta 1 integrin-mediated tyrosine phosphorylation in human T cells: characterization of Crk- and Fyn-associated substrates (pp105, pp115, and human enhancer of filamentation-1) and integrin-dependent activation of p59fyn1.
Integrin adhesion receptors transduce signals that transmit information from the extracellular environment to the cell interior. Although integrins lack intrinsic tyrosine kinase activity, stimulation of the alpha 4 beta 1 integrin on human H9 T cells results in rapid tyrosine phosphorylation of proteins in the 105 to 115 kDa range. In this study, we report that alpha 4 integrin stimulation of H9 T cells results in tyrosine phosphorylation of three distinct proteins: pp105, pp115, and human enhancer of filamentation 1 (HEF1), all of which associate with the adapter protein c-Crk. However, pp115 can be distinguished from pp105 and HEF1 by its ability to associate with the SH2 domain of the tyrosine kinase p59fyn. Both pp105 and pp115 are antigenically distinct from HEF1, p130Cas, pp125FAK, Pyk2, p120cbl, and the p110 subunit of phosphatidylinositol 3-kinase. The functional significance of pp115 association with p59fyn is suggested by the ability of alpha 4 integrin stimulation to activate Fyn tyrosine kinase activity. These studies show that alpha 4 integrin stimulation of T cells results in the tyrosine phosphorylation of several distinct substrates. The association of these substrates with intracellular signaling intermediates, such as Crk and Fyn, may play a critical role in integrin-mediated regulation of T cell function.


Factors affecting quality of life in cancer patients undergoing chemotherapy.
Cancer can produce many different symptoms, some subtle and some not at all subtle. An increasingly important issue in oncology is to evaluate quality of life (QoL) in cancer patients. The cancer-specific QoL is related to all stages of this disease. The aim of this study was to evaluate the QoL in cancer patients with solid tumors and at the different chemotherapy cycles (CT). This was a cross-sectional study. A total of 200 cancer patients were included. With some modification, the European Organization for Research and Treatment of Cancer QoL Questionnaire (EORTC QLQ-C30) was used to measure QoL in the patients. The QoL in most subjects (66%) was fairly favorable. A significant relationship between the cancer type, pain intensity, and fatigue was found. However, none of the demographic variables (age, education, marital status, income) were significantly related to QoL. Nevertheless, significant difference was found between the level of QoL in patients with ≤ 2 CT cycles and/or with 3-5 cycles (p< 0.001). Cancer is an important health issue influencing QoL. An appropriate treatment which may provide care to the cancer patients is CT. A CT cycle may improve QoL in patients with solid tumors.


Stromatoporoid growth rhythms and rates.
Stromatoporoids are major contributors to framework construction in Paleozoic reefs. The Devonian species Parallellostroma densilaminata (Fagerstrom), P. winchelli (Galloway and Ehlers), and Stictostroma sp. form large rhythmically structured colonies that competitively overgrow corals. Their competitive interactions and important role as reef builders place considerable value on growth rate information. Identification of common growth periods in these interacting species provides a methodfor quantifying vertical and lateral stromatoporoid growth and a means for identifying an annual periodicity of calcification.


Pharmacokinetic comparisons of bepotastine besilate and bepotastine salicylate in healthy subjects.
Bepotastine is a second-generation histamine H(1) receptor antagonist that is indicated in allergic rhinitis, urticaria, and pruritus associated with skin disease. The aim of the present study was to compare the pharmacokinetics of two different bepotastine formulations [bepotastine besilate 10 mg (reference) and bepotastine salicylate 9.64 mg (test)], both containing 7.11 mg bepotastine base, to satisfy regulatory requirements for marketing. A single-center, randomized, single-dose, open-label, two-period, two-sequence crossover study with a 7-day washout period was conducted in 26 healthy male subjects. Plasma samples for drug analysis were collected up to 24 h after drug treatment. Pharmacokinetic parameters, including maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC), were calculated. ANOVA for bioequivalence was conducted using log-transformed C(max) and AUC values, and the mean ratios and their 90 % confidence intervals were calculated. Of the 26 participants initially enrolled, 24 healthy participants completed both treatment periods. All pharmacokinetic parameters of bepotastine exhibited no significant differences between the two formulations. The observed mean (standard deviation) C(max), AUC from time zero to the time of the last measurable concentration (AUC(last)), and AUC from time zero to infinity (AUC(∞)) values for the reference formulation were 99.9 (31.4) ng/mL, 388.9 (102.6) ng·h/mL, and 392.4 (103.6) ng·h/mL, respectively. Corresponding values for the test formulation were 101.0 (26.3) ng/mL, 389.8 (112.2) ng·h/mL, and 393.7 (111.7) ng·h/mL. The geometric mean ratios (90 % CI) between the two formulations were 1.0220 (0.9224-1.1324) for C(max), 0.9928 (0.9521-1.0351) for AUC(last), and 0.9959 (0.9549-1.0387) for AUC(∞). During the study period, two adverse events were reported in the test formulation group, but both were transient, mild, and resolved completely during the treatment period. These adverse events were considered unrelated to the study drugs. The results of the present study revealed that bepotastine besilate 10 mg (reference) and bepotastine salicylate 9.64 mg (test) formulations have comparable pharmacokinetic characteristics and that these two formulations meet the regulatory criteria for bioequivalence. Both bepotastine formulations were generally well-tolerated in this population.


Promoting Excellence and Reflective Learning in Simulation (PEARLS): development and rationale for a blended approach to health care simulation debriefing.
We describe an integrated conceptual framework for a blended approach to debriefing called PEARLS [Promoting Excellence And Reflective Learning in Simulation]. We provide a rationale for scripted debriefing and introduce a PEARLS debriefing tool designed to facilitate implementation of the new framework. The PEARLS framework integrates 3 common educational strategies used during debriefing, namely, (1) learner self-assessment, (2) facilitating focused discussion, and (3) providing information in the form of directive feedback and/or teaching. The PEARLS debriefing tool incorporates scripted language to guide the debriefing, depending on the strategy chosen. The PEARLS framework and debriefing script fill a need for many health care educators learning to facilitate debriefings in simulation-based education. The PEARLS offers a structured framework adaptable for debriefing simulations with a variety in goals, including clinical decision making, improving technical skills, teamwork training, and interprofessional collaboration.


Experimental demonstration of an optical-sectioning compressive sensing microscope (CSM).
In this paper we present the design and implementation of a Compressive Sensing Microscopy (CSM) imaging system, which uses the Compressive Sensing (CS) method to realize optical-sectioning imaging. The theoretical aspect of the proposed system is investigated using the mathematical model of the CS method and an experimental prototype is constructed to verify the CSM design. Compared to conventional optical-sectioning microscopes (such as Laser Scanning Confocal Microscopes (LSCMs) or Programmable Array Microscopes (PAMs)), the CSM system realizes optical-sectioning imaging using a single-pixel photo detector and without any mechanical scanning process. The complete information of the imaging scene is reconstructed from the CS measurements numerically.


Hepatitis C treatment outcome in relation to alcohol consumption and racial differences in southeastern Taiwan.
Alcohol use may have negative impacts on hepatitis C virus (HCV) treatment due to low adherence, and racial differences can influence HCV sustained virological response (SVR) rate between East Asian and European ancestry. The objective of this study is to confirm the influence of alcohol consumption and racial differences on HCV treatment outcome in aboriginal and nonaboriginal people of southeastern Taiwan. In this retrospective cohort study, a total of 195 patients were treated with peginterferon-alpha once weekly plus ribavirin for 24 weeks. The efficacy analysis was performed based on the SVR rate for patients who received at least one dose of the study medication or who completed treatment. The endpoints were denoted by virological response rate including the influences of alcohol use, HCV genotype, serum level of HCV virological load, and racial differences. No differences were observed in the baseline clinical characteristics between drinkers and nondrinkers, but a significant difference was noted in the body mass index between aboriginal and nonaboriginal populations (28.3 vs. 25.8; p < 0.01). With respect to the SVR rate, no difference was found between drinkers and nondrinkers, and between aboriginal and nonaboriginal people. The treatment efficacy of SVR in the whole group was significantly different between patients with HCV genotype 1 and nongenotype 1 (73.5% vs. 91.2%; p < 0.01). An analysis of the SVR rate in the aboriginal group showed no significant difference between patients with genotype 1 and nongenotype 1 (80.0% vs. 91.3%; p = 0.31). In southeastern Taiwan, alcohol consumption did not influence the HCV treatment outcome, and the SVR rates were similar between patients with HCV genotype 1 and nongenotype 1 infections in the aboriginal group.


A Comparative Study on the Postpartum Depression of Vietnamese Marriage Immigrant Women and Korean Women.
This study aimed to examine postpartum depression of Vietnamese married immigrant women and Korean women, and to identify factors that affect postpartum depression. Subjects of one hundred and thirty-five women who had delivered a baby within 3 years were part of the study. Of these women, sixty were Vietnamese married immigrant women and sixty -seven were Korean women living in Gangwon Province. Kim's (2005) Korean version of Cox's (1987) EPDS (Edinburgh Postnatal Depression Scale) was used to evaluate postpartum depression. The reliability of the entire subjects was Cronbach's alpha=.677, Vietnamese women .743, and Korean women .654. There were significant differences between the two groups in demographic data and obstetric history. There were significant differences in EPDS (t=-0.236, p=.814) of the type of household between the two groups. Korean women experienced more depression in the items of EPDS 1,2,5, and Vietnamese women experienced more depression in the items of EPDS 7, 8, and 10 when comparing item by item. The influencing factors of EPDS in entire subjects were marriage type, satisfaction of relationship with the husband and other household extended family members, and emotional experience during pregnancy. Postpartum depression has occurred regardless of ethnicity, therefore prevention programs targeted at depression, and family support programs should be developed for all childbearing women.


Oesophageal cancer: caregiver mental health and strain.
To investigate strain and mental health among family caregivers of oesophageal cancer patients and possible factors associated with caregiver mental health and strain. Patients with oesophageal adenocarcinoma in Ireland were recruited into the FINBAR study (the main aim of which was to investigate factors influencing the Barrett's adenocarcinoma relationship). Carers completed the 13-item Caregiver Strain Index and the General Health Questionnaire-30 (GHQ) in the context of a brief interview with trained research staff that was undertaken separately from the interview with each cancer patient. Two hundred and twenty-seven patients participated in the FINBAR study. A total of 39 patients did not have a family carer or the carer could not be identified. Fifty percent (94/188) of carers completed the questionnaires. Mean (SD) scores for strain (6.65, SD=3.63) and mental health status (10.21, SD=7.30) were high and 71% of carers scored >5 on the GHQ indicating psychological distress. There was a statistically significant positive relationship between level of strain experienced by caregivers and the severity of their mental health status and whether or not carers scored >5 on the GHQ. Relatives were 1.70 (95% CI 1.34-2.15) times more likely to be defined as high scorers with each unit increase in the CSI score. A significant proportion of caregivers experienced high levels of strain and psychological distress. There is a need to provide appropriate support and services targeted specifically at reducing the considerable strain of caring for patients with oesophageal cancer, particularly for carers of patients from lower socioeconomic groups.


The activity of creatine kinase in frog skeletal muscle studied by saturation-transfer nuclear magnetic resonance.
1. The activity of creatine kinase in intact anaerobic frog muscle at 4 degrees C at rest and during contraction was investigated by using saturation-transfer 31P n.m.r. 2. At rest, the measured forward (phosphocreatine to ATP) reaction flux was 1.7 X 10(-3) M . s-1 and the backward flux was 1.2 X 10(-3) M . s-1. The large magnitude of both fluxes shows that creatine kinase is active in resting muscle, so the observed constancy of [phosphocreatine] demonstrates that the enzyme and its substrates are at equilibrium. 3. The apparent discrepancy between the fluxes must arise largely from an underestimation of the backward flux resulting from interaction of ATP with other systems, e.g. via adenylate kinase. For purposes of further calculation we have therefore adopted 1.6 X 10(-3) M . s-1 as an estimate of both fluxes. 4. During contraction, when the creatine kinase reaction is no longer at equilibrium, the net rate of phosphocreatine breakdown, estimated directly from the change in area of the inorganic phosphate peak, was 0.75 X 10(-3) M . s-1. Saturation transfer indicates that the forward reaction flux remains at approx. 1.6 X 10(-3) M . s-1 and the backward flux decreases to about 0.85 X 10(-3) M . s-1. 5. The activity of creatine kinase during contraction is large enough to account for the well-established observation that, during contraction, the concentration of ATP falls by less than 2-3%. The reaction catalysed by creatine kinase is driven forward during contraction by the large relative increase in the concentration of free ADP, which is more than doubled. 6. The observation that the forward flux does not increase during contraction and that the backward flux decreases can most simply be explained on the basis of competition of reactants for a limited amount of enzyme.


Neonatal BCG vaccination and child survival in TB-exposed and TB-unexposed children: a prospective cohort study.
To assess the association between neonatal BCG vaccination and mortality between 28 days and 3 years of age among tuberculosis (TB)-exposed and TB-unexposed children. Prospective cohort study. Bandim Health Project runs an urban Health and Demographic Surveillance site in Guinea-Bissau with registration of mortality, vaccination status and TB cases. Children entered the analysis when their vaccination card was inspected after 28 days of age and remained under surveillance to 3 years of age. Children residing in the same house as a TB case were classified as TB-exposed from 3 months prior to case registration to the end of follow-up. Using Cox-proportional hazards models with age as underlying time scale, we compared mortality of children with and without neonatal BCG between October 2003 and September 2017. HR for neonatal BCG compared with no neonatal BCG by TB-exposure status. Among the 39 421 children who entered the analyses, 3022 (8%) had observation time as TB-exposed. In total, 84% of children received neonatal BCG. Children with neonatal BCG had lower mortality both in TB-exposed (adjusted HR: 0.57 (0.26 to 1.27)) and in TB-unexposed children (HR: 0.57 (95% CI 0.47 to 0.69)) than children without neonatal BCG. Children exposed to TB had higher mortality than TB-unexposed children if they had not received neonatal BCG. Neonatal BCG vaccination was associated with lower mortality among both TB-exposed and TB-unexposed children, consistent with neonatal BCG vaccination having beneficial non-specific effects. Interventions to increase timely BCG vaccination are urgently warranted.


Growth rates of Florida corals from 1937 to 1996 and their response to climate change.
Ocean acidification causes declines in calcification rates of corals because of decreasing aragonite saturation states (Ω(arag)). Recent evidence also indicates that increasing sea surface temperatures may have already reduced growth and calcification rates because of the stenothermic threshold of localized coral populations. Density banding in coral skeletons provides a record of growth over the coral's lifespan. Here we present coral extension, bulk density and calcification master chronologies from seven subtropical corals (Montastraea faveolata) located in the Florida Keys, USA with a 60-year common period, 1937-1996. Linear trends indicate that extension increased, density decreased and calcification remained stable while the most recent decade was not significantly different than decadal averages over the preceding 50 years for extension and calcification. The results suggest that growth rates in this species of subtropical coral have been tolerant to recent climatic changes up to the time of collection (1996).


Cushioning the cartilage: a canonical Wnt restricting matter.
Wnt signalling pathways have key roles in joint development, homeostasis and disease, particularly in osteoarthritis. New data is starting to reveal the importance of tightly regulating canonical Wnt signalling pathway activation to maintain homeostasis and health in articular cartilage. In addition to the presence of different Wnt antagonists that limit pathway activation in articular cartilage, the reciprocal crosstalk between the canonical and non-canonical cascades and competitive antagonism between different Wnt ligands seem to be critical in restraining excessive Wnt pathway activation. Changes in transcriptional complex assembly upon Wnt pathway activation, epigenetic modulation of target gene transcription, in particular through histone modifications, and complex interactions between the Wnt signalling pathway and other signalling pathways, are also instrumental in adjusting Wnt signalling. In this Review, the cellular and molecular mechanisms involved in fine-tuning canonical Wnt signalling in the joint are updated, with a focus on the articular cartilage. The interventions for preventing or treating osteoarthritis are also discussed, which should aim to limit disease-associated excessive canonical Wnt activity to avoid joint damage.


Inferring multi-locus selection in admixed populations.
Admixture, the exchange of genetic information between distinct source populations, is thought to be a major source of adaptive genetic variation. Unlike mutation events, which periodically generate single alleles, admixture can introduce many selected alleles simultaneously. As such, the effects of linkage between selected alleles may be especially pronounced in admixed populations. However, existing tools for identifying selected mutations within admixed populations only account for selection at a single site, overlooking phenomena such as linkage among proximal selected alleles. Here, we develop and extensively validate a method for identifying and quantifying the individual effects of multiple linked selected sites on a chromosome in admixed populations. Our approach numerically calculates the expected local ancestry landscape in an admixed population for a given multi-locus selection model, and then maximizes the likelihood of the model. After applying this method to admixed populations of Drosophila melanogaster and Passer italiae, we found that the impacts between linked sites may be an important contributor to natural selection in admixed populations. Furthermore, for the situations we considered, the selection coefficients and number of selected sites are overestimated in analyses that do not consider the effects of linkage among selected sites. Our results imply that linkage among selected sites may be an important evolutionary force in admixed populations. This tool provides a powerful generalized method to investigate these crucial phenomena in diverse populations.


Complete Genome Sequence of Clostridium perfringens LLY_N11, a Necrotic Enteritis-Inducing Strain Isolated from a Healthy Chicken Intestine.
Clostridium perfringens strain LLY_N11, a commensal bacterium, which previously induced necrotic enteritis in an experimental study, was isolated from the intestine of a young healthy chicken. Here, we present the complete genome sequence of this strain, which may provide a better understanding of the molecular mechanisms involved in necrotic enteritis pathogenesis.


The efficacy of twice daily cephalexin.
A multi-centre study in general practice was carried out to compare the efficacy of two doses of cephalexin-500 mg or 1 g - given in a twice daily dosage regimen to 752 patients with respiratory or soft tissue infections. After 5-days' treatment, over 80% of the patients were cured or considerably improved, with no differences between the two treatment groups. Considering the lower respiratory and soft tissue infections together, 1 g cephalexin twice daily produced a better clinical response after 48-hours' treatment, suggesting a more rapid response with the higher dosage, but this trend did not reach statistical significance. Twice daily cephalexin therapy was also effective in patients with concurrent illness, and in those patients who had been treated unsuccessfully with other antibacterial therapy in the week prior to trial entry. No drug interactions were reported and the incidence of side-effects was low.


The neuroprotective effects of hydro-alcoholic extract of olive (Olea europaea L.) leaf on rotenone-induced Parkinson's disease in rat.
Parkinson's disease (PD) is an age-related disease in which dopaminergic neurons in the nigrostriatal pathway are destroyed, resulting in movement and behavioral problems. Oxidative stress and the generation of reactive oxygen species play key roles in neurodegenerative diseases, such as PD. Rotenone (ROT) is a common pesticide that induces oxidative stress. Olive leaves extract (OLE) has antioxidant and neuroprotective effects. Thus, the aim of this study was to investigate the neuroprotective effects of OLE on ROT-induced oxidative stress in the midbrain of a rat model of PD. Ninety-six Wistar rats were randomly divided into the following 6 groups (n = 16 rats/group): Control, Sham, ROT, and 3 ROT + OLE (75, 150, and 300 mg/kg/daily) groups. ROT (2.5 mg/kg/48 h) was injected subcutaneously, and vehicle or OLE was orally administered for 30 days. The animals were then sacrificed, and their brains were removed. Biochemical measures, including the levels of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and malondialdehyde (MDA), and the number of tyrosine hydroxylase (TH)-positive neurons were determined, and behavioral (rotarod and hanging) tests were conducted. The balance and muscle strength of the OLE (150 and 300 mg/kg)-treated groups were significantly improved. Treatment with OLE prevented the increases in the levels of MDA, significantly improved the SOD, CAT, and GPx levels in the midbrain, and prevented the depletion of the TH-positive neurons. These findings suggested that OLE has neuroprotective properties and that it might be useful for preventing the death of dopaminergic neurons in patients with PD.


Extracorporeal apheresis therapy for Alzheimer disease-targeting lipids, stress, and inflammation.
Current therapeutic approaches to Alzheimer disease (AD) remain disappointing and, hence, there is an urgent need for effective treatments. Here, we provide a perspective review on the emerging role of "metabolic inflammation" and stress as a key factor in the pathogenesis of AD and propose a novel rationale for correction of metabolic inflammation, increase resilience and potentially slow-down or halt the progression of the neurodegenerative process. Based on recent evidence and observations of an early pilot trial, we posit a potential use of extracorporeal apheresis in the prevention and treatment of AD. Apolipoprotein E, lipoprotein(a), oxidized LDL (low density lipoprotein)'s and large LDL particles, as well as other proinflammatory lipids and stress hormones such as cortisol, have been recognized as key factors in amyloid plaque formation and aggravation of AD. Extracorporeal lipoprotein apheresis systems employ well-established, powerful methods to provide an acute, reliable 60-80% reduction in the circulating concentration of these lipid classes and reduce acute cortisol levels. Following a double-membrane extracorporeal apheresis in patients with AD, there was a significant reduction of proinflammatory lipids, circulating cytokines, immune complexes, proinflammatory metals and toxic chaperones in patients with AD. On the basis of the above, we suggest designing clinical trials to assess the promising potential of such "cerebropheresis" treatment in patients with AD and, possibly, other neurodegenerative diseases.


Background synaptic activity modulates the response of a modeled purkinje cell to paired afferent input.
We studied the possible effects of background excitatory and inhibitory synaptic activity on Purkinje cell responses to paired pulse inputs using a morphologically and physiologically detailed compartmental model. Paired-pulse inputs were provided via synapses associated with the ascending segment of the granule cell axon in the presence of variable amounts of background synaptic input provided by parallel fibers and inhibitory interneurons. The results predict the amplitude and dynamics of the somatic and dendritic responses to paired ascending segment inputs are modulated by the level of background synaptic activity, the basal somatic firing rate of the Purkinje cell model does not indicate the type or degree of modulation, and the modulatory effects are mediated through dendritic calcium and calcium-activated potassium currents. These results have important consequences for the functional organization of cerebellar cortex as well as the more general issue of the modulatory as distinct from driving effects of synapses now also being considered in other regions of the mammalian brain including the cerebral cortex.


Therapy with women with metastatic breast cancer.
To describe some clinical issues encountered in individual and group therapy with women with metastatic breast cancer. The pressure to 'keep positive' poses dilemmas for patients and therapists alike, whether in individual or group therapy. The basis of skilled supportive care rests on the ability of therapists to assist patients and their families to face death rather than avoid it. Paradoxically, facing issues of death and dying leads to a greater sense of control, and empowers patients to reorder life's priorities, thus improving quality of life and relationships. In addition to the obvious need to detect and treat illness such as depression, working with women with metastatic breast cancer requires flexibility on the part of the therapist to adapt to her physical state of health, to include partners and family members where possible, and to liaise with colleagues in the treating team to facilitate communication and understanding of specific difficulties that may be encountered.


Availability of emergency obstetric care (EmOC) among public and private health facilities in rural northwest Bangladesh.
Although safe motherhood strategies recommend that women seek timely care from health facilities for obstetric complications, few studies have described facility availability of emergency obstetric care (EmOC). We sought to describe and compare availability and readiness to provide EmOC among public and private health facilities commonly visited for pregnancy-related complications in two districts of northwest Bangladesh. We also described aspects of financial and geographic access to healthcare and key constraints to EmOC provision. Using data from a large population-based community trial, we identified and surveyed the 14 health facilities (7 public, 7 private) most frequently visited for obstetric complications and near misses as reported by women. Availability of EmOC was based on provision of medical services, assessed through clinician interviews and record review. Levels of EmOC availability were defined as basic or comprehensive. Readiness for EmOC provision was based on scores in four categories: staffing, equipment, laboratory capacity, and medicines. Readiness scores were calculated using unweighted averages. Costs of C-section procedures and geographic locations of facilities were described. Textual analysis was used to identify key constraints. The seven surveyed private facilities offered comprehensive EmOC compared to four of the seven public facilities. With 100% representing full readiness, mean EmOC readiness was 81% (range: 63%-91%) among surveyed private facilities compared to 67% (range: 48%-91%) in public facilities (p = 0.040). Surveyed public clinics had low scores on staffing and laboratory capacity (69%; 50%). The mean cost of the C-section procedure in private clinics was $77 (standard deviation: $16) and free in public facilities. The public sub-district facilities were the only facilities located in rural areas, with none providing comprehensive EmOC. Shortages in specialized staff were listed as the main barrier to EmOC provision in public facilities. Although EmOC availability and readiness was higher among the surveyed seven most commonly visited private clinics, public facilities appeared to be more affordable for C-section and more geographically accessible. Strategies to retain anesthesiologists and surgeons, such as non-financial incentives, are needed to improve EmOC provision in the public sector. Centralized blood banks are recommended to streamline safe blood acquisition for obstetric surgeries.


Production of sexed bovine embryos in vitro can be improved by selection of sperm treatment and co-culture system.
The study investigated the effects of sperm sorting, capacitation treatment and co-cultivation on sexed bovine in vitro embryo production. The effect of treatment and co-culture on production of embryos of the preferred sex from unsorted sperm was also studied. Sperm from five breeding bulls was used for fertilization of mature oocytes as follows: Experiment 1, sorted and unsorted sperm (bulls A-E) treated only with heparin in standard co-cultures; Experiment 2, sorted sperm (bulls A-E) treated with heparin-PHE (penicillamine, hypotaurine, and epinephrine) or heparin-caffeine in drop co-cultures; and Experiment 3, unsorted sperm (bull E) treated with either heparin-PHE or heparin-caffeine in both standard and drop co-cultures. In all bulls, treatment with heparin resulted in significantly (p < .05) reduced cleavage and blastocyst rates from sorted sperm, as compared with those from unsorted sperm. In bulls A, B, D and E, treatment of sorted sperm with heparin-PHE in drops significantly increased the blastocyst rate (p < .05). In unsorted sperm of bull E, heparin-PHE treatment in drops resulted in the XX/XY sex ratio inverse to that obtained by heparin-caffeine treatment in standard co-cultures (32.3%/67.7% and 66.7%/33.3%, respectively). In conclusion, the treatment of sorted sperm with heparin-PHE in modified drop co-cultures can be recommended for production of in vitro sexed embryos. The use of unsorted sperm for production of embryos of the preferred sex by selected capacitation treatment and co-culture can be the method of choice in bulls with low IVF yields from sorted sperm.


Differential expression of transforming growth factor beta receptors in human pancreatic adenocarcinoma.
Many cancer cells show resistance to transforming growth factor beta (TGF-beta)-mediated growth inhibition. This resistance to TGF-beta is associated with an increased tumorigenic phenotype. In this study, we determined whether a loss in expression of TGF-beta receptors or DPC4, an important down stream target of TGF-beta signaling, might account for this lack of TGF-beta sensitivity in pancreatic adenocarcinoma. To accomplish this, six established pancreatic cancer cell lines, twenty-six surgically resected tumor specimens of pancreatic adenocarcinoma and ten non-tumor pancreas tissues were analyzed for the mRNA expression of the three TGF-beta receptors (RI, RII, and RIII) and DPC4. We report here that five of six pancreatic cancer cell lines were not sensitive to TGF-beta. All the ten non-tumor specimens of pancreas showed expression of RI, and DPC4; while nine of ten showed expression of RIII and eight of ten showed expression of RII. Five of six pancreatic cancer cell lines and 23 of 26 tumor specimens showed expression of RI. Two cell lines and about half (46%) of the tumor specimens did not express RII. Only two cell lines showed appreciable levels of RIII expression; while ten of 26 (38%) tumor specimens did not show expression of RIII. DPC4 expression was observed in three of the six (50%) cell lines and 19 of 24 (79%) tumor specimens. This study indicates that apart from the functional loss of DPC4 due to mutations or homozygous deletion, a lack of the TGF-beta receptors, particularly RII and RIII, may contribute to a loss of TGF-beta signaling in a population of pancreatic cancers.


New insights in celiac disease.
Celiac disease (CD) is an autoimmune disorder occurring in genetically susceptible subjects. The incidence of CD is around 1%, and it is much more common in first-degree relatives of CD patients, 10%-18%. However, the pattern of the genetic inheritance is still obscure. Environmental factors are undoubtedly affecting the disease's clinical presentation, time at presentation, and may have an effect on the characteristics of the disease. The clinical presentation of CD has shifted during the previous decades from the classical presentation in which the toddler suffers from diarrhea, constipation, vomiting, failure to thrive, abdominal distension, etc., to the child with a monosymptomatic presentation, such as anemia, as well as an enlarged list of extra-intestinal disorders. The diagnosis of CD is being established by symptoms consistent with CD and positive serology. The ultimate diagnosis should be made upon histological evaluation of the small bowel mucosa. The treatment of CD is a lifelong, strict gluten-free diet (GFD). Compliance with a GFD is quite difficult. Therefore, new strategies for prevention and treatment modalities other than GFD are greatly needed. Recently several promising therapeutic modalities have been developed; these include resuming traditional baking techniques. Another methodology is using probiotic-driven prolylendopeptidase. Another pathway to tackle the therapeutic option in CD is by down-regulation of the activity of zonulin-the active pump enabling gluten to enter the enterocytes. We are facing an era where other modalities beyond a GFD might allow CD patients to be able to tolerate occasionally a small amount of gluten in their diet.


Frequency, presentation, and outcome of Takayasu arteritis in Western Australia.
Takayasu arteritis (TAK) is large-vessel vasculitis that predominantly affects young women. There is worldwide variation in the frequency of TAK depending on genetic and/or environmental factors. With Australian data lacking, we describe the epidemiology, clinical features and outcomes of TAK in Western Australia (WA). Retrospective case cohort study of incident TAK cases between 1 January 2000 and 30 June 2015 in WA identified from multiple sources. Data on disease presentation and outcome were extracted from medical records. Eighteen patients received a clinical diagnosis with thirteen cases meeting 1990 ACR criteria for TAK (all female, 77% Caucasian, age at diagnosis 39 years) included in this analysis. Per million inhabitants the annual incidence and prevalence (2015) was 0.3 and 3.2 for Caucasians and 1.1 and 15 for Asians. Limb claudication and bruit were commonest symptoms; ESR or CRP was raised in 61% at diagnosis while aortic involvement Hata type IIb most prevalent (30%). Despite general combination therapy with corticosteroids and immunosuppressant drugs, four patients suffered a stroke, two patients developed myocardial infarction, and five patients required vascular intervention. Three Caucasian patients died during the study period. TAK is much more prevalent in the Asian than Caucasian population of WA and associates with significant long-term morbidity and mortality despite standard therapy.


A Critical Care Standpoint in the Diagnosis of Scleroderma Renal Crisis.
Typical or atypical presentations of rare diseases may be confounded by co-morbidities in critically-ill patients. It is imperative to diagnose and treat appropriately, despite this difficulty. Scleroderma renal crisis mimics many other conditions, and can be potentially fatal if not caught early enough. Particularly, in critically-ill patients with multiple pathologies, it can be difficult to distinguish scleroderma renal crisis from other diseases, such as thrombotic thrombocytopenic purpura (TTP), hypertensive emergency, posterior reversible encephalopathy syndrome (PRES), or atypical hemolytic uremic syndrome (HUS). Herein, a patient who presented with encephalopathy and seizures was initially treated for thrombotic thrombocytopenic purpura, but was ultimately diagnosed with scleroderma renal crisis. Given her numerous laboratory abnormalities, such as thrombocytopenia, hemolytic anemia, kidney and liver dysfunction, and elevated inflammatory markers, various differentials were considered. During her hospitalization, she suffered a cardiac arrest, seizures, nosocomial infections and worsening kidney disease requiring dialysis, making the final diagnosis of scleroderma renal crisis a diagnosis of exclusion. Subsequently, the management of a patient with multiple co-morbidities and confounding laboratory abnormalities difficult to treat. This article highlights these intricacies and formulates the thought process behind the diagnosis of Scleroderma Renal Crisis.


Comparing Vitamin D Supplementation Versus Placebo for Urgency Urinary Incontinence: A Pilot Study.
To estimate the efficacy of vitamin D supplementation to reduce urgency urinary incontinence (UUI) episodes. Pilot, two-arm, randomized trial conducted from 2013 to 2017. Interventions were 12 weeks of weekly oral 50,000 IU vitamin D3 or placebo. Academic, university-based outpatient clinic. Community-dwelling postmenopausal women, 50 years or older, with at least three UUI episodes on 7-day bladder diary and serum vitamin 25-hydroxyvitamin D (25[OH]D) of 30 ng/mL or less. The primary efficacy estimate was the percentage change in UUI episodes. Secondary estimates included changes in other lower urinary tract symptoms, along with exploratory subgroup analysis by race/ethnicity and obesity. We randomized 56 women (aged 50-84 years; mean = 60.5 ± 8.2 years), 28 to vitamin D and 28 to placebo; 51 completed treatments. Mean serum 25(OH)D at baseline (21.2 ± 5.2 and 18.2 ± 5.6, P = .30) improved to 57.9 ± 16.3 ng/mL with vitamin D3 and 21.9 ± 8.2 ng/mL with placebo (P < .001). UUI episodes per 24-hour day decreased by 43.0% with vitamin D3 compared to 27.6% with placebo (P = .22). Among black women (n = 33), UUI episodes decreased by 63.2% with vitamin D3 compared to 22.9% with placebo (P = .03). Among obese women, UUI episodes decreased by 54.1% with vitamin D compared to 32.7% with placebo (P = .29). For all women, changes in voiding frequency (P = .40), nocturia (P = .40), urgency (P = .90), incontinence severity (P = .81), and overactive bladder symptom severity (P = .47) were not different between arms. Postmenopausal women with UUI and vitamin D insufficiency demonstrated a greater than 40% decrease in UUI episodes, which did not reach statistical significance compared to placebo, except in the subset of black women. The results of this pilot study support further investigation of vitamin D3 alone or in combination with other treatments for UUI, particularly for women in higher-risk subgroups. J Am Geriatr Soc 67:570-575, 2019.


[Cervical and intracranial arterial dissection: review of the acute clinical presentation and imaging of 48 cases].
Arterial dissections result from longitudinal tear of the vessel wall produced by an intramural haematoma. We have retrospectively review 48 consecutive patients with 53 arterial dissections diagnosed by cerebral angiography and/or magnetic resonance imaging. Arterial dissections were extracranial in 88% (carotid in 58% and vertebral in 30%) and intracranial in 12% of cases, with 19% of multiple dissections. Extracranial dissections presented with infarct (82%) (major 52%, multifocal 16%, focal 28% e watershed 4%), cervical pain and/or headache (38%) incomplete Horner syndrome (14%). The intracranial dissections presented with infarct, intracranial hypertension and hydrocephalus, subarachnoid hemorrhage and brain haematoma. Most common angiographic findings in the extracranial carotid dissections were stenosis with slow flow (66%), occlusion (34%) and dissecting aneurysm (7%). In the extracranial vertebral dissections the angiograms depicted stenosis with slow flow (82%), occlusion (18%) and dissecting aneurysm (18%). In the intracranial dissections stenosis and dissecting aneurysm were equally found. Extracranial arterial dissections have are an important cause of stroke in the younger population. Anti thrombotic drugs are used for the treatment of dissections presenting with infarct. Refractory extracranial dissections and intracranial dissection with haemorrhage presentation and/or dissecting aneurysms should be managed by endovascular treatment.


Coordination Chemistry of Bifunctional Chemical Agents Designed for Applications in 64Cu PET Imaging for Alzheimer's Disease.
Positron emission tomography (PET) is emerging as one of the most important diagnostic tools for brain imaging, yet the most commonly used radioisotopes in PET imaging, 11C and 18F, have short half-lives, and their usage is thus somewhat limited. By comparison, the 64Cu radionuclide has a half-life of 12.7 h, which is ideal for administering and imaging purposes. In spite of appreciable research efforts, high-affinity copper chelators suitable for brain imaging applications are still lacking. Herein, we present the synthesis and characterization of a series of bifunctional compounds (BFCs) based on macrocyclic 1,4,7-triazacyclononane and 2,11-diaza[3.3](2,6)pyridinophane ligand frameworks that exhibit a high affinity for Cu2+ ions. In addition, these BFCs contain a 2-phenylbenzothiazole fragment that is known to interact tightly with amyloid β fibrillar aggregates. Determination of the protonation constants (pKa values) and stability constants (log β values) of these BFCs, as well as characterization of the isolated copper complexes using X-ray crystallography, electron paramagnetic resonance spectroscopy, and electrochemical studies, suggests that these BFCs exhibit desirable properties for the development of novel 64Cu PET imaging agents for Alzheimer's disease.


Synthetic peptide vaccine against mucosal colonization by group A streptococci. I. Protection against a heterologous M serotype with shared C repeat region epitopes.
M protein is an antigenically variable virulence determinant present on the surface of group A streptococci, and it provides the basis for the serologic typing scheme. Type-specific serum antibodies afford strong protection against infection by the homologous serotype. Non-type-specific antigenic epitopes also exist within the surface-exposed portion of M protein. Previous studies demonstrated that intranasal immunization with Ag corresponding to sequences within the non-type-specific pepsin-susceptible site and adjacent C repeat regions of M6 protein, evoke protective immunity against pharyngeal colonization by type 6 streptococci in a mouse model. Although the protective immunogens are not type-specific, the pepsin site region of M6 is shared among less than 20% of serotypes examined. Therefore it was necessary to determine whether more highly conserved M protein epitopes elicit mucosal protection against group A streptococci, and if protective immunity extends to heterologous serotypes. In this report, peptides were synthesized that correspond to sequences completely contained within the highly conserved C repeat region of M6 protein. Peptide Ag were covalently coupled to the mucosal adjuvant, cholera toxin B subunit (CTB), and mice immunized intranasally and orally with peptide-CTB conjugates were compared to control groups that received CTB only. Immunization with the peptide-CTB conjugates led to significant protection against pharyngeal colonization by group A streptococci. Furthermore, protection was observed against the heterologous M serotype, type 14. These findings suggest that protection against multiple serotypes of group A streptococci can be achieved with a vaccine consisting of the widely shared C repeat region of M6 protein.


The mechanical performance of the standard Hoffmann-Vidal external fixation apparatus.
A standard Hoffmann-Vidal quadrilateral fixation system for tibial fractures was analyzed using different geometric and material variations of the basic configuration. The fixation stiffness properties were quantitated to provide objective comparison. The results have shown that the bone-pin interface is the least-stiff link in the entire structure, particularly under the anterior-posterior bending mode. Rigidity of the device can be substantially improved by increasing the number of pins, using full threaded pins with a larger diameter, decreasing side connecting-rod distances, and increasing pin-separation distances in each pin group. Symmetrical tightening of the compression screws by hand is sufficient to produce compression of bone at the fracture site. The use of titanium pins tends to reduce stiffness, but using a frame made of titanium can significantly decrease the weight of the apparatus without decreasing its stiffness.


Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer.
Although a high level of thymidylate synthase (TS) expression in malignant tumours has been suggested to be related to a reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in non-small cell lung cancer (NSCLC). We have now investigated the effect of TS overexpression on pemetrexed sensitivity in NSCLC cells. We established NSCLC cell lines that stably overexpress TS and examined the effects of such overexpression on the cytotoxicity of pemetrexed both in vitro and in xenograft models. We further examined the relation between TS expression in tumour specimens from NSCLC patients and the tumour response to pemetrexed by immunohistochemical analysis. The sensitivity of NSCLC cells overexpressing TS to the antiproliferative effect of pemetrexed was markedly reduced compared with that of control cells. The inhibition of DNA synthesis and induction of apoptosis by pemetrexed were also greatly attenuated by forced expression of TS. Furthermore, tumours formed by TS-overexpressing NSCLC cells in nude mice were resistant to the growth-inhibitory effect of pemetrexed observed with control tumours. Finally, the level of TS expression in tumours of non-responding patients was significantly higher than that in those of responders, suggestive of an inverse correlation between TS expression and tumour response to pemetrexed. A high level of TS expression confers a reduced sensitivity to pemetrexed. TS expression is thus a potential predictive marker for response to pemetrexed-based chemotherapy in NSCLC patients.


Platinum vaporization-deposition coated polycarbonate membranes for comprehensive, multimodal, and correlative microscopic analysis of micro-and nanoplastics and other environmental particles.
Anthropogenic particles, including microplastics, are receiving ever-increasing concern due to their potential environmental impact. Surveys and monitoring require sampling from many environmental and biological matrices, including natural water, drinking water, sediment, and air. However, there are no standard methods for sampling particles in the environment; thereby, many different approaches are used for both single particle and ensemble distribution or bulk chemical analyses. In the microplastics field, particles are often analyzed on membranes using automated analysis with spectroscopic techniques such as Fourier-transform infrared spectroscopy (FTIR) and Raman spectroscopy. For automated analysis, the filters' properties are crucial. We coated polycarbonate (PC) membranes with 100 nm platinum (Pt) on both side using a e-beam evaporator and evaluated their suitability for filtrating and analysis of environmental samples. The PC membranes have a defined and practical pore size, available in many pore sizes and with circular diameter of 47 mm and 25 mm. Our Pt coated membranes can handle large volumes of fresh and marine waters, high pressure, and various treatment solutions. Moreover, they have good optical properties for imaging with light microscopy (LM) and Scanning Electron Microscopy (SEM), and no disturbing background signal for Raman or FTIR spectroscopy analysis.


Periapical healing after apicocurettage during apexification.
A case is presented in which conventional apexification with CaOH-CMCP paste was not successful at first. A minimal apicocurettage was done. Subsequently, the periapical bone healed and a dry, hard apical stop formed at the apical foramen. A gutta percha root canal filling was packed from the coronal access. This procedure offered a surgical alternative to an alloy retrofilling, when the usual apexification process was not successful.


Screen time is associated with depression and anxiety in Canadian youth.
This study examined the relationships between screen time and symptoms of depression and anxiety in a large community sample of Canadian youth. Participants were 2482 English-speaking grade 7 to 12 students. Cross-sectional data collected between 2006 and 2010 as part of the Research on Eating and Adolescent Lifestyles (REAL) study were used. Mental health status was assessed using the Children's Depression Inventory and the Multidimensional Anxiety Scale for Children-10. Screen time (hours/day of TV, video games, and computer) was assessed using the Leisure-Time Sedentary Activities questionnaire. Linear multiple regressions indicated that after controlling for age, sex, ethnicity, parental education, geographic area, physical activity, and BMI, duration of screen time was associated with severity of depression (β=0.23, p<0.001) and anxiety (β=0.07, p<0.01). Video game playing (β=0.13, p<.001) and computer use (β=0.17, p<0.001) but not TV viewing were associated with more severe depressive symptoms. Video game playing (β=0.11, p<0.001) was associated with severity of anxiety. Screen time may represent a risk factor or marker of anxiety and depression in adolescents. Future research is needed to determine if reducing screen time aids the prevention and treatment of these psychiatric disorders in youth.


High-frequency mobilization of broad-host-range plasmids into Neisseria gonorrhoeae requires methylation in the donor.
Antibiotic resistance in Neisseria gonorrhoeae has been associated with the acquisition of R plasmids from heterologous organisms. The broad-host-range plasmids of incompatibility groups P (IncP) and Q (IncQ) have played a role in this genetic exchange in nature. We have utilized derivatives of RSF1010 (IncQ) and RP1 (IncP) to demonstrate that the plethora of restriction barriers associated with the gonococci markedly reduces mobilization of plasmids from Escherichia coli into strains F62 and PGH 3-2. Partially purified restriction endonucleases from these gonococcal strains can digest RSF1010 in vitro. Protection of RSF1010-km from digestion by gonococcal enzymes purified from strain F62 is observed when the plasmid is isolated from E. coli containing a coresident plasmid, pCAL7. Plasmid pCAL7 produces a 5'-MECG-3' cytosine methylase (M.SssI). The M.SssI methylase only partially protects RSF1010-km from digestion by restriction enzymes from strain PGH 3-2. Total protection of RSF1010-km from PGH 3-2 restriction requires both pCAL7 and a second coresident plasmid, pFnuDI, which produces a 5'-GGMECC-3' cytosine methylase. When both F62 and PGH 3-2 are utilized as recipients in heterospecific matings with E. coli, mobilization of RSF1010 from strains containing the appropriate methylases into the gonococci occurs at frequencies 4 orders of magnitude higher than from strains without the methylases. Thus, protection of RSF1010 from gonococcal restriction enzymes in vitro correlates with an increase in the conjugal frequency. These data indicate that restriction is a major barrier against efficient conjugal transfer between N. gonorrhoeae and heterologous hosts.


[Evaluation of hematopoietic and stromal cells-precursors in children with neutropenia].
The content of hemopoietic and stromal precursor-cells was studied in the bone marrow of 46 children with congenital neutropenia and of 2 children with chronic benign neutropenia. It was found that the number of GM-CFC and F-CFC in the bone marrow of patients with chronic benign neutropenia did not differ from that in the control group of normal children, and the lowering of the neutrophil number in the blood was, probably, associated with their redistribution mechanism or increased destruction in the body. Multiple defects of hemopoietic and stromal tissue were detected in children with a hereditary form of congenital neutropenia when anomalous proliferation of F-CFC and disorders in GM-CFC differentiation led to hypoplasia of granulocytic growth stem and neutropenia.


Attrition in patients with single ventricle and trisomy 21: outcomes after a total cavopulmonary connection.
Data are limited regarding the management of children with trisomy 21 (T21) syndrome and a functional single ventricle (FSV). We evaluated patients with T21 and a FSV who had a total cavopulmonary connection (TCPC). From September 1999 to August 2012, 139 patients with a FSV underwent a TCPC. Sixty-five had unbalanced atrioventricular septal defect. Thirteen had T21. Three (of 13) had heterotaxy syndrome. The mean age at the Fontan operation was 27.6 ± 12.1 months. The initial procedure was pulmonary artery banding in 9 patients, systemic-to-pulmonary shunt in 2 and Damus-Kaye-Stansel/Norwood procedure in 2. Median follow-up was 69 months (interquartile range 25-75, 21-99). There was 1 death after a Damus-Kaye-Stansel/Norwood procedure and one interstage death after a bidirectional Glenn procedure. Nine (of 11) survivors underwent a Fontan operation. A fenestrated Fontan procedure was the predominate operation in 78%. One patient was deemed unsuitable for a Fontan operation. There was 1 takedown and 1 late death after the Fontan operation. Heterotaxy syndrome did not affect outcome ( P > 0.05). There was no statistical difference in the pre-Fontan McGoon ratio, hospital length of stay, duration of pleural drainage and Fontan-related adverse events between patients with a dominant right ventricle and those with a left ( P > 0.05). A TCPC in patients with T21 and an FSV is associated with reproducible, satisfactory outcomes. An assisted-Glenn procedure with pulsatile pulmonary blood flow and a fenestrated Fontan may be associated with attenuated perioperative morbidity and late attrition.


Development of necrosis and activation of disease resistance in transgenic tobacco plants with severely reduced catalase levels.
Numerous studies argue that salicylic acid (SA) is an important component of the plant signal transduction pathway(s) leading to disease resistance. The discovery that the SA-binding protein is a catalase, whose activity is blocked by SA, led to the proposal that one of SA's modes of action is to inhibit this H2O2-degrading enzyme and thus elevate H2O2 levels. To test this model, an attempt was made to mimic the action of SA by reducing the synthesis of catalase using antisense RNA technology. Analyses of transgenic tobacco plants that expressed the tobacco catalase 1 (cat1) or catalase 2 (cat2) gene in an antisense orientation indicate that there is no correlation between modest to high levels of reduction in catalase activity and activation of plant defenses such as pathogenesis-related (PR)-1 protein synthesis. However, three independent antisense catalase transgenic plants (ASCAT1 Nos 16, 17, and 28), which exhibited the most severe reduction in catalase activity (approximately 90% or more), developed chlorosis or necrosis on some of their lower leaves. These same leaves accumulated very high levels of PR-1 proteins and showed enhanced resistance to tobacco mosaic virus. Necrosis and elevated SA, which appear to result from severe depression of catalase levels, may be responsible for the induction of these defense responses.


Ridge augmentation with guided bone regeneration and GTAM case illustrations.
The principle of Guided Bone Regeneration (GBR) can be used for Ridge Augmentation. These case illustrations describe the technique using Autogenous Cortico-Cancellous Bone Grafts and stabilization with Miniscrews and placement of a GTAM Barrier Membrane. Nyman et al (1990) published the first report of enlargement of a reduced alveolar ridge. Becker & Becker, Jovanovic, Buser et al have documented successful regeneration of such ridges. A study by Lang et al established that: 1. An undisturbed healing period of at least six months is required for optimal bone regeneration. 2. Smaller defects (less than 70 mm.3) regenerate almost completely. 3. Larger defects (greater than 90 mm.3) regenerate 90-93 percent and bone grafts may enhance success in larger defects. 4. Premature membrane removal will result in incomplete regeneration. Buser et al have described the technique of GBR in detail. They found the creation and maintenance of a secluded space is essential for successful outcome with GBR procedures. This space allows for the in growth of osteogenic cells so that bone regeneration is undisturbed by competing non-osteogenic soft tissue cells. Space-making defects such as extraction sockets are simple to treat, but localized ridge augmentation may be difficult because the membrane is not supported by bony walls. E-PTFE membranes have been reinforced with titanium struts and mini screws have been developed as a way of dealing with membrane collapse. Buser et al began to utilize autogenous bone grafts to support the membrane and to act as an osseoinductive scaffold for bone regeneration. They utilized a cortico-cancellous block graft in the centre of the augmentative area with smaller chips to fill in the periphery. The cortical portion of the graft re-establishes the buccal cortex and the cancellous portion is placed against the host bone. The host bone is perforated to open the marrow spaces. Placement of membrane protects the bone graft (up to 50 percent of grafted bone is lost through resorption in augmentation procedures where membrane is not used).


A comparison of inflammatory mediator expression between palmoplantar pustulosis and pompholyx.
Both palmoplantar pustulosis (PPP) and pompholyx are clinically characterized by acute eruptions of vesicles or pustules on the palms or soles. This study aims to compare the expression of certain inflammatory mediator genes and proteins between patients with PPP and pompholyx using skin tissue samples. Skin biopsies obtained from lesional skin from patients with PPP (n = 7) and pompholyx (n = 5) were analysed by quantitative RT-PCR to measure the mRNA levels of nine genes, including IL-4, IL-8, IL-9, IL-17, IL-22, IFN-γ, CCL-20, granzyme and perforin. For immunohistochemical analysis, 34 paraffin-embedded skin specimens (PPP, n = 22; pompholyx, n = 12) were stained with anti-IL-8, IL-17A, IL-22 and granzyme B antibodies. Of genes analysed, IL-8 and IL-17A mRNA expression levels were significantly higher in the PPP group than the pompholyx group (P = 0.012 in both), whereas the mRNA expression of granzyme B was significantly higher in pompholyx when compared with PPP (P = 0.004). Regarding the IL-17A immunohistochemical staining, tissue from the PPP lesions contained significantly more IL-17A(+) cells in both the epidermis and papillary dermis when compared with pompholyx (P < 0.001 and P = 0.019 respectively). Moreover, the intensity of the IL-8 immunoreactivity was also greater in the PPP skin lesions than the pompholyx tissue (P < 0.001). IL-8 and IL-17A, both are increased in PPP tissue, may represent important immunologic mediators that help to differentiate this clinical entity from pompholyx. This study may provide useful clues in distinguishing PPP from pompholyx, as well as helping to understand the pathogeneses of these two diseases.


Percutaneous laser disc decompression versus conventional microdiscectomy for patients with sciatica: Two-year results of a randomised controlled trial.
Background Percutaneous laser disc decompression is a minimally invasive treatment, for lumbar disc herniation and might serve as an alternative to surgical management of sciatica. In a randomised trial with two-year follow-up we assessed the clinical effectiveness of percutaneous laser disc decompression compared to conventional surgery. Materials and methods This multicentre randomised prospective trial with a non-inferiority design, was carried out according to an intent-to-treat protocol with full institutional review board approval. One hundred and fifteen eligible surgical candidates, with sciatica from a disc herniation smaller than one-third of the spinal canal, were randomly allocated to percutaneous laser disc decompression ( n = 55) or conventional surgery ( n = 57). The main outcome measures for this trial were the Roland-Morris Disability Questionnaire for sciatica, visual analogue scores for back and leg pain and the patient's report of perceived recovery. Results The primary outcome measures showed no significant difference or clinically relevant difference between the two groups at two-year follow-up. The re-operation rate was 21% in the surgery group, which is relatively high, and with an even higher 52% in the percutaneous laser disc decompression group. Conclusion At two-year follow-up, a strategy of percutaneous laser disc decompression, followed by surgery if needed, resulted in non-inferior outcomes compared to a strategy of microdiscectomy. Although the rate of reoperation in the percutaneous laser disc decompression group was higher than expected, surgery could be avoided in 48% of those patients that were originally candidates for surgery. Percutaneous laser disc decompression, as a non-surgical method, could have a place in the treatment arsenal of sciatica caused by contained herniated discs.


Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer.
To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m(2) once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarone's test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.


Immunohistochemical detection of P-glycoprotein in formalin-fixed and paraffin-embedded normal and neoplastic canine tissues.
Expression of P-glycoprotein, a phylogenetically conserved integral plasma membrane protein, is implicated as one of the most important factors contributing to tumor cell multidrug resistance. Formalin-fixed, paraffin-embedded normal and neoplastic canine tissues were studied using an avidin-biotin complex technique employing three murine monoclonal antibodies (C494, C219, JSB-1) to different epitopes of the P-glycoprotein molecule. Evaluation of immunostaining of normal canine tissues revealed positive labeling detected by each antibody in the liver, proximal renal tubular epithelium, adrenal cortex, colonic epithelium, and capillary endothelial cells of the brain. A total of 166 tumors of epithelial or mesenchymal origin were evaluated for P-glycoprotein immunoreactivity. Hepatomas (4/4), colorectal adenomas (7/7), colorectal carcinomas (4/4), adrenal cortical adenomas (3/3), hemangiopericytomas (15/15), apocrine gland adenocarcinomas (4/5, 80%), and transitional cell carcinomas (2/2) consistently labeled with at least one of the antibodies. Histiocytomas (0/10), cutaneous plasma cell tumors (0/10), fibromas (0/3), fibrosarcomas (0/4), and leiomyomas (0/4) were uniformly negative with all antibodies. Malignant lymphomas (6/22, 27.3%), malignant melanomas (4/13, 30.8%), leiomyosarcomas (3/6, 50%), mammary gland carcinomas (12/19, 63.2%), mammary gland adenomas (3/9, 33.3%), squamous cell carcinomas (8/10, 80%), basal cell tumors (5/7, 71.4%), apocrine gland adenomas (1/2, 50%), cholangiocarcinomas (2/3, 66.7%), and thyroid gland carcinomas (2/4, 50%) gave variable results. The antibodies C494, JSB-1, and C219 labeled 66/166 (39.8%), 53/166 (31.9%), and 38/166 (22.9%) of all tumors studied, respectively. A total of 26/166 (15.7%), 22/166 (13.3%), and 37/166 (22.6%) of tumors were labeled by all three, just two, or one antibody alone, respectively. The antibody C494 was the only antibody labeling 28/166 (16.9%) of the cases. JSB-1 alone labeled 9/166 (5.4%) of the tumors. C219 failed to label any tumors not also labeled by either C494 or JSB-1. Labeling by C494 was more intense and specific than labeling by the other two antibodies. Results indicate that P-glycoprotein can be detected in routinely processed canine tissues. The detection of P-glycoprotein within canine liver, kidney, adrenal gland, and colon and within tumors arising from these tissues is consistent with that reported in the literature for human tissues. Variable labeling results of other tumors such as malignant lymphoma and mammary gland carcinomas also is consistent with reports of human studies. Detection of multidrug resistance markers such as P-glycoprotein in canine tissues may provide additional information upon which to base a prognosis or to design treatment regimens for canine tumors.