Variations in Hormones and Antioxidant Status in Relation to Flowering in Early, Mid, and Late Varieties of Date Palm (Phoenix dactylifera) of United Arab Emirates.
The present study was carried out to assess the status of various hormones responsible for the flower induction of Nagal, Lulu, and Khalas date palm varieties in UAE. The nonenzymatic antioxidant compounds and the antioxidant enzymatic activities at preflowering, flowering, and postflowering stages of the date palm varieties were quantified. The ABA and zeatin concentrations were found to be significantly higher during the preflowering stage but gradually decreased during the flowering period and then increased after the flowering stage. Gibberellic acid (GA) concentrations were significantly higher in the early flowering varieties and higher levels of ABA may contribute to the delayed flowering in mid and late varieties. The results on hormone profiling displayed a significant variation between seasons (preflowering, flowering, and postflowering) and also between the three date palms (early, mid, and late flowering varieties). Ascorbic acid (AA) concentration was low at the preflowering stage in the early flowering Nagal (0.694 mg/g dw), which is similar with the late flowering Lulu variety (0.862 mg/g dw). However, Khalas variety showed significantly higher amount of AA content (7.494 mg/g dw) at the preflowering stage when compared to other varieties. In flowering stage, Nagal (0.814 mg/g dw) and Lulu (0.963 mg/g dw) were similar with respect to the production of AA, while the mid flowering variety showed significantly higher amount of AA (9.358 mg/g dw). The Khalas variety produced the highest tocopherol at 4.78 mg/g dw compared to Nagal and Lulu, at 1.997 and 1.908 mg/g dw, respectively, during the preflowering stage. In Nagal variety, the content of reduced glutathione (GSH) at the preflowering stage was 0.507 mg/g dw, which was not significantly different from the flowering and postflowering stages at 0.4 and 0.45 mg/g dw, respectively. The GSH was significantly higher in Khalas compared to Nagal and Lulu varieties, at 1.321 mg/g w in the preflowering phase followed by 3.347 mg/g dw and 2.349 mg/g dw at the flowering and postflowering phases, respectively. Catalase activity increased with different stages of growth. The lowest catalase activity was observed at the preflowering stage in Khalas (0.116), with similar observations noted during flowering (0.110) and postflowering stage. This study provides an insight into the possible roles of endogenous hormones and antioxidants and in the activities of antioxidant enzymes in the regulation of flower development in date palm varieties.


Two-Step Screening for Depressive Symptoms and Prediction of Mortality in Patients With Heart Failure.
Comorbid depression in patients with heart failure is associated with increased risk for death. In order to effectively identify depressed patients with cardiac disease, the American Heart Association suggests a 2-step screening method: administering the 2-item Patient Health Questionnaire first and then the 9-item Patient Health Questionnaire. However, whether the 2-step method is better for predicting poor prognosis in heart failure than is either the 2-item or the 9-item tool alone is not known. To determine whether the 2-step method is better than either the 2-item or the 9-item questionnaire alone for predicting all-cause mortality in heart failure. During a 2-year period, 562 patients with heart failure were assessed for depression by using the 2-step method. With the 2-step method, results are considered positive if patients endorse either depressed mood or anhedonia on the 2-item screen and have scores of 10 or higher on the 9-item screen. Screening results with the 2-step method were not associated with all-cause mortality. Patients with scores positive for depression on either the 2-item or 9-item screen alone had 53% and 60% greater risk, respectively, for all-cause death than did patients with scores negative for depression after adjustments for covariates (hazard ratio, 1.530; 95% CI, 1.029-2.274 for the 2-item screen; hazard ratio, 1.603; 95% CI, 1.079-2.383 for the 9-item screen). The 2-step method has no clear advantages compared with the 2-item screen alone or the 9-item screen alone for predicting adverse prognostic effects of depressive symptoms in heart failure.


Old versus new medications: how much should be taught?
To address the issue of how much psychiatric residents should be taught about older medications. Selective use of the literature, including historical overview, was employed to compare and contrast old and newer generation medications. While many old drugs are truly antiquated, medications such as typical antipsychotics, tricyclic and monoamine oxidase antidepressants, and lithium should remain integral parts of a psychopharmacology teaching program. A proper blending of knowledge about older and newer medications and the use of older and newer medications is in the best interest of patients in need of psychopharmcotherapy.


Opioid contracts in chronic nonmalignant pain management: objectives and uncertainties.
In this article, we review the principal objectives and ideal elements of opioid contracts, as articulated by proponents of the practice. We examine the limited empirical evidence for the effectiveness of opioid contracts in achieving their intended objectives and identify areas of uncertainty and of ethical concern regarding their implementation. We argue that the challenge in deciding about implementing opioid contracts in clinical practice relates to the multiplicity of potential objectives they might serve, to a lack of empirical evidence regarding their effectiveness, and to ethical concerns over their implementation. Specialty and primary care clinicians contemplating the use of opioid contracts in treating patients with chronic nonmalignant pain need to be sensitive to these considerations, and further debate and research is necessary to establish the proper objectives, elements, effectiveness, and ethical justifications of opioid contracts in clinical practice.


[Diagnostic significance of the spinal-brain stem polysynaptic reflex and the period of inhibition].
Electrical stimulation of the radial nerve associated with voluntary contraction of the shoulder girdle inhibited bioelectrical activity not only in the muscles of the hypothenar but also in the proximal muscles. In resting muscles, such stimulation elicited a reflex response with a large latent period. With weak voluntary tension stimulation elicited a reflex response while in the presence of considerable contraction the reflex response merged with bioelectrical activity, with a clearly demonstrable subsequent period of inhibition. The current viewpoint about the antidromal blockade of the segmental motoneurons is debated. It is suggested that the polysynaptic reflex and the inhibition period are connected with the same level of realization -- the oral portions of the brain stem.


Materials: solidification and ostwald ripening of near-monotectic zinc-lead alloys.
Studies of melting and resolidification were carried out on Spacelab 1 on the zinc-lead binary, an alloy which exhibits a miscibility gap in the liquid state. The possibility of maintaining the state of homogeneous dispersion of lead in the zinc matrix in a microgravity environment was verified. The second objective of the experiment was to study Ostwald ripening of the lead droplets (manifested as slow coarsening of the droplets) within the region of immiscibility. An increase in droplet size was observed and may have been due to Ostwald ripening, although the effect on droplet size of precipitation during cooling must be analyzed before this can be determined conclusively.


Simple capillary electrophoresis-mass spectrometry method for complex glycan analysis using a flow-through microvial interface.
A flow-through microvial is used to interface capillary electrophoresis and mass spectrometry (CE-MS) to develop a method for simultaneous profiling both neutral and sialylated glycans without derivatization or labeling. The CE separation was performed at near-zero electroosmotic flow in a capillary with neutral, hydrophilic coating, using 50 mM ammonium acetate in 20% methanol (pH 3.1) as the background electrolyte. The method was optimized with reversed CE polarity and negative ion ESI-MS. Enzymatically released N-glycans from human immunoglobulin G (IgG) were used as the test sample. The approach was also used to study the more complex N-glycans from recombinant human erythropoietin (rHuEPO) expressed in Chinese hamster ovary (CHO) cells. Glycoscreening of rHuEPO was performed using a triple quadrupole MS and an ultrahigh resolution TOF-MS. The high sensitivity and high mass accuracy of the TOF-MS revealed the presence of more than 70 glycans. Three mono- and di-sialylated tetra-antennary N-glycans and one mono-sialylated tri-antennary N-glycan of rHuEPO are reported for the first time. Further glycan heterogeneity was identified of the highly sialylated N-glycans of rHuEPO by extensive acetylation, Neu5Ac/Neu5Gc variation and the presence of N-acetyl-lactosamine repeats. For comparative purposes, porous graphitic carbon-based LC-MS/MS was also used to glycoprofile rHuEPO. This work demonstrates the potential of CE-MS to provide a comprehensive glycosylation profile with detailed features of the secondary glycan modifications. The CE-MS based method eliminates the need to label the N-glycans, as well as the requirement to desialylate before analysis, and could complement other established techniques for glycan characterization of therapeutic glycoproteins.


Identification and functional characterization of NbMLP28, a novel MLP-like protein 28 enhancing Potato virus Y resistance in Nicotiana benthamiana.
Major latex proteins (MLPs) belong to the MLP subfamily in Bet v 1 protein family and respond to both biotic and abiotic stresses, which play critical roles in plant disease resistance. As the type species of widely distributed and economically devastating Potyvirus, Potato virus Y (PVY) is one of the major constraints to important crop plants including tobacco (Nicotiana benthamiana) worldwide. Despite the great losses owing to PVY infection in tobacco, there is no previous study investigating the potential role of MLPs in developing resistance to viral infection. In this study, for the first time we have identified and functionally analyzed the MLP-like protein 28 from N. benthamiana, denoted as NbMLP28 and investigated its role in conferring resistance to N. benthamiana against PVY infection. NbMLP28 was localized to the plasmalemma and nucleus, with the highest level in the root. NbMLP28 gene was hypothesized to be triggered by PVY infection and was highly expressed in jasmonic acid (JA) signaling pathway. Further validation was achieved through silencing of NbMLP28 through virus-induced gene silencing (VIGS) that rendered N. benthamiana plants more vulnerable to PVY infection, contrary to overexpression that enhanced resistance. Taken together, this is the first study describing the role of NbMLP28 in tobacco against PVY infection and provide a pivotal point towards obtaining pathogen-resistant tobacco varieties through constructing new candidate genes of MLP subfamily.


On the neighborhoods of trees.
Tree rearrangement operations typically induce a metric on the space of phylogenetic trees. One important property of these metrics is the size of the neighborhood, that is, the number of trees exactly one operation from a given tree. We present an exact expression for the size of the TBR (tree bisection and reconnection) neighborhood, thus answering a question first posed by Allen and Steel . In addition, we also obtain a characterization of the extremal trees whose TBR neighborhoods are maximized and minimized.


Effect of soil surface salt on the density and distribution of the snail Bithynia siamensis goniomphalos in northeast Thailand.
Opisthorchis viverrini infection is associated with human cholangiocarcinoma and northeast Thailand has the highest incidence of this disease in the world. Bithynia siamensis goniomphalos is the major freshwater snail intermediate host of O. viverrini in this area and an analysis based on geographical information systems was used to determine the effect of variation in soil surface salt on the density and distribution of this snail. A malacological survey was carried out in 56 water bodies in the Khorat basin, northeast Thailand at locations with various soil surface salt levels. Mollusk samples were collected from 10 ecologically representative water body sites with 10-20 sampling stations in each. The shoreline of clear, shallow water bodies was found to be the preferred B. s. goniomphalos habitat. The snails were exclusively found in water with salinity levels ranging between 0.05 and 22.11 parts per thousand (ppt), which supports the notion that B. s. goniomphalos prefers water with some saline content over pure, freshwater. The highest snail population densities were in rice fields, ponds, road-side ditches and canals within a water salinity range of 2.5-5.0 ppt. However, the presence of B. s. goniomphalos was negatively correlated with water salinity (P ≤0.05), both with regard to density and distribution. The areas with the highest density of B. s. goniomphalos were those with less than 1% soil surface salt (potential index = 0.314), while the lowest densities were found in areas exceeding 50% soil surface salt (potential index = 0.015).


Percutaneous treatment of thrombosed arteriovenous fistulas: clinical and economic implications.
Maintenance of previously thrombosed arteriovenous fistulas (AVFs) as functional vascular accesses can be highly expensive, with relevant financial implications for healthcare systems. The aim of our study was to evaluate the costs and health outcomes of vascular access care in hemodialysis patients with AVF thrombosis. A retrospective, controlled cohort study was performed among local hemodialysis patients with completely thrombosed AVFs between August 1, 2007, and July 1, 2008. Detailed clinical and demographic information was collected and a comprehensive measure of total vascular access costs was obtained. Costs are reported in 2009 U.S. dollars. A total of 63 consecutive hemodialysis patients with thrombosed AVFs were identified--a cohort of 37 patients treated with percutaneous thrombectomy and a historic cohort of 25 patients with abandoned thrombosed AVFs. The mean cost of all vascular access care at 6 months was $2479. Salvage of thrombosed AVFs led to a near two-fold reduction in access-related expenses, per patient-month at risk ($375 versus $706; P = 0.048). The costs for access-related hospitalizations ($393 versus $91; P = 0.050), management of access dysfunction ($106 versus $28; P = 0.005), and surgical interventions ($35 versus $6; P = 0.001) were also significantly lower in the percutaneous treatment group. At 6 months, most of these patients had a functional AVF as permanent vascular access (91% versus 33%, P = 0.0001). Salvage of thrombosed AVF is a highly efficient procedure; therefore, intensive efforts should be undertaken to universalize these interventions.


An assessment of knowledge and attitudes towards amongst leprosy/Hansen's disease workers in Guyana.
Background leprosy is still prevalent in certain parts of the world, particularly India and South America. In order to reduce the associated stigma, it was renamed Hansen's disease, although the associated prejudice and social stigma are thought to remain obstacles to its eradication. This study, set in Guyana, aims to assess attitudes, ideas and knowledge of the disease amongst healthcare workers. A self-completing questionnaire was designed and distributed amongst healthcare workers in both Georgetown Central Hospital and Suddi Hospital over a 4-week period in September 2000. The information was then collated and analysed using STATA 6.0. A total of 185 questionnaires were completed and returned. They showed that knowledge of the disease was relatively good, but that certain facts were not widely known. For example, half the respondents did not know that leprosy is now curable, many thought it could be transmitted through touch. Although most respondents did not display prejudice in their own responses, many implied that prejudice was still present in the wider community. A significant minority believed that patients should be kept apart from other people. It is evident from the study that some prejudices and misconceptions still exist. In order to reduce this, an emphasis needs to be placed on education regarding transmission and the low rate of infectivity of leprosy; that it is not spread by touch and is now curable, also that, if treated in the early stages, it has a very good prognosis. It is these areas which health education should focus upon.


Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury.
Profound hepatocellular injury is often a consequence of adenovirus-mediated gene therapy or acetaminophen ingestion. The aim of the present study was to examine the role of a CXC chemokine, macrophage inflammatory protein-2 (MIP-2), in the hepatotoxic response by mice infected with adenovirus and challenged with acetaminophen. CD1 mice that received a replication-defective human type 5 adenovirus vector (Ad70-3) intravenously exhibited hepatic injury that peaked at 24 h after infection. In contrast, mice that received a similar adenovirus vector containing a rodent MIP-2 cDNA insert had no hepatic injury at any time after infection. The combination of Ad70-3 infection and an intraperitoneal challenge with 400 mg/kg of acetaminophen was fatal in 50% of the mice, but only 10% of the AdMIP-2 group receiving acetaminophen were similarly affected. Furthermore, AdMIP-2 mice had significantly lower hepatic injury and serum aminotransaminases compared with the Ad70-3 group. However, AdMIP-2 infection in mice lacking the CXC chemokine receptor that binds MIP-2, CXCR2, did not attenuate any of the markers of liver injury after adenovirus and acetaminophen challenge. AdMIP-2 treatment of CD1 mice was also associated with significantly decreased leukocyte infiltration into the liver and an earlier increase in hepatic 3H-thymidine incorporation compared with the control group. Taken together, these data demonstrate that MIP-2 has a protective role in both adenovirus- and acetaminophen-mediated hepatotoxicity, and suggest that MIP-2 may promote rapid hepatic regeneration following acute hepatic injury.


Translation efficiency in yeasts correlates with nucleosome formation in promoters.
Elongation efficiency index (EEI) was suggested earlier to estimate gene expression efficiency by nucleotide context of coding sequence in unicellular organisms. We have analyzed association between EEI and nucleosome formation potential (NFP) in 5' regulatory regions upstream translation initiation site (TIS) from two yeast species. Theoretical estimations of NFP based on DNA sequence were obtained by Recon method. Experimental estimation of nucleosome occupancy was obtained by high-throughput sequencing data of nucleosomal DNA in Saccharomyces cerevisiae . For the sample of all genes correlation coefficient was calculated between two vectors: vector of NFP values for fixed position relative to TIS and vector of EEI values. Profiles of correlation coefficients of NFP and EEI were counted in (-600; +600) regions relative to TIS for gene sequences extracted from GenBank. We found regions of strong negative dependence between NFP and EEI for all genes as well as for 10% highly expressed genes in Schizosaccharomyces pombe (10% of EEI-highest genes). At the same time, we found positive dependence between NFP and EEI for all genes and for low expressed genes in S. cerevisiae (10% of EEI-lowest genes). The association between NFP and EEI could be explained by evolutionary selection of context characteristics of nucleotide sequences for gene expression optimization.


Heterogeneity of genetic control of blood pressure in ethnically different populations.
We review the literature on statistical genetic analyses of blood pressure in samples from various ethnic backgrounds using different statistical methods and packages. We then provide the results of a complex segregation analysis performed on familial data on systolic and diastolic blood pressure in 2 ethnically different populations, Chuvashans and Turkmenians. Two types of major gene models were tested in the segregation analysis: Model type 1 tests for a Mendelian mode of transmission and estimates genotype-specific averages regardless of age and sex effect, and model type 2 estimates age and sex effects on each of 3 genotypes within the putative major genotype. In both total samples, by both types of segregation analysis, familial aggregation of both systolic and diastolic blood pressure was inconsistent with the Mendelian mode of inheritance. In the next step of analysis the pedigrees in both samples were sorted into 2 groups on the basis of 2 likelihoods as obtained under Mendelian and nontransmission models for each entire sample. This procedure resulted in the appearance of 2 subsamples (large and small) in each ethnic sample. The segregation analysis that was carried out then on the larger subsample provided consistent evidence to support the major gene effect on systolic and diastolic blood pressure in 2 ethnic groups. Interestingly, model type 2 showed that in both ethnically different large subsamples, for each sex the genotype predisposing to a larger mean value of systolic (or diastolic) blood pressure also displayed the highest rate of blood pressure increase with age. We discuss in detail possible sources of heterogeneity in familial transmission of blood pressure observed in our 2 samples, and we suggest a method to improve the analysis of heterogeneity for trait inheritance.


[Immunopathology of chronic obstructive pulmonary disease].
Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable condition that has a complex pathophysiology and an even more complex immunopathological process. The purpose of this review was to analyze COPD immunopathological aspects, which was addressed by undertaking a literature search for the most relevant documents indexed in the PubMed database over the last 10 years. Different conclusions could be drawn: in COPD immunopathology there are immune and non-immune inflammatory changes with oxidative stress imbalance, there are alterations in the protease/anti-protease ratio caused by direct and indirect genetic and epigenetic-environmental defects; COPD produces irreversible tissue damage and chronic inflammation with tissue repair alteration, which induces chronic obstruction of the airway, bronchitis and systemic damage. Most common resulting comorbidities include cardiovascular disease, metabolic syndrome, osteoporosis, depression, musculoskeletal dysfunction, increased biological age, lung cancer and other types of malignancies. In the conception of COPD, recognizing that it is a non-transmittable and preventable disease is indispensable.


Serum liver fatty acid binding protein shows good correlation with liver histology in NASH.
Simple, reproducible and non-invasive tests that can be used to determine the severity of non-alcoholic steatohepatitis (NASH) are needed. Liver-type fatty acid binding protein (L-FABP) plays a key role in the fatty acid metabolism of the liver. We aimed to determine whether serum L-FABP levels in patients with NASH were different from those in healthy controls, and if so, whether this was associated with the degree of fibrosis, steatosis and inflammatory activity. Forty-seven patients with histologically confirmed NASH and 41 healthy controls were included in the study. Serum L-FABP levels were measured in all participants. Mean L-FABP levels were significantly higher in patients with NASH compared to the control group (2703.19±1603.47 vs. 1684.58±860.19, p<0.001). Serum L-FABP levels showed a significant positive correlation with NAS score (p=0.03, r=0.312), the degree of fibrosis (p=0.02, r=0.324) and inflammation (p=0.03, r=0.312), BMI (p=0.05, r=0.303), serum ALT (p=0.01, r=0.28), AST (p=0.04, r=0.315), and triglyceride levels (p=0.03, r=0.328). Serum L-FABP levels are elevated in NASH and this elevation is positively correlated with the degree of fibrosis and inflammation. L-FABP levels may aid as a non-invasive marker in determining the severity of fibrosis and inflammation in patients with NASH.


Adaptations to infer fitness interdependence promote the evolution of cooperation.
The evolution of cooperation is a major question in the biological and behavioral sciences. While most theoretical studies model cooperation in the context of an isolated interaction (e.g., a Prisoner's Dilemma), humans live in heterogeneous social environments, characterized by large variations in fitness interdependence-the extent to which one's fitness is affected by others. Theoretical and experimental work indicates that humans can infer, and respond to, variations in interdependence. In a heterogeneous ancestral environment, these psychological mechanisms to infer fitness interdependence could have provided a selective advantage, allowing individuals to maximize their fitness by deciding when and with whom to cooperate. Yet, to date, the link between cognitive inference, variation in fitness interdependence, and cooperation remains unclear. Here we introduce a theoretical framework to study the evolution of inference and cooperation in heterogeneous social environments, where individuals experience interactions with varying levels of corresponding interests. Using a combination of evolutionary game theory and agent-based modeling, we model the evolution of adaptive agents, who incur a cost to infer interdependence, in populations of fixed-behavior agents who always cooperate or defect. Our results indicate that natural selection could promote the evolution of psychological mechanisms to infer fitness interdependence, provided that there is enough variation in fitness interdependence to offset the cost of inference. Under certain conditions, the fixation of adaptive agents results in higher levels of cooperation. This depends crucially on the type of inference performed and the features of the interdependence landscape.


Comparison of biokinetics and biliary imaging parameters of four Tc-99m iminodiacetic acid derivatives in normal subjects.
The biokinetics (blood clearance, urinary excretion, hepatic peak time, uptake, and excretion t-1/2) and the imaging parameters (the time of appearance of the common bile duct, gallbladder, and duodenum) were determined in 34 normal subjects using Tc-99m diethyl (EIDA), Tc-99m dimethyl (HIDA), Tc-99m paraisopropyl (PIPIDA), and Tc-99m parabutyl (PBIDA) iminodiacetic acid derivatives. The blood and hepatic clearance of the four agents were significantly different (P less than 0.05) from each other. The 24-hour urinary excretion of PBIDA was significantly lower (P less than 0.05) than the urinary excretion of the other three agents. There was no difference among the four agents in the time of appearance of the gallbladder and duodenum. The time of appearance of the common bile duct was significantly delayed with PBIDA. The maximum intensity of the common bile duct usually occurred between 20 to 40 minutes with all four agents. However, gallbladder intensity continued to increase up to 3 hours. It is concluded that in the presence of normal liver function, all four Tc-99m IDA agents show definite differences in biokinetics but these differences do not have a major effect on biliary imaging parameters. If imaging alone is the primary goal, the selection of any one of the four agents will meet the clinican's need satisfactorily.


Local euchromatin enrichment in lamina-associated domains anticipates their repositioning in the adipogenic lineage.
Interactions of chromatin with the nuclear lamina via lamina-associated domains (LADs) confer structural stability to the genome. The dynamics of positioning of LADs during differentiation, and how LADs impinge on developmental gene expression, remains, however, elusive. We examined changes in the association of lamin B1 with the genome in the first 72 h of differentiation of adipose stem cells into adipocytes. We demonstrate a repositioning of entire stand-alone LADs and of LAD edges as a prominent nuclear structural feature of early adipogenesis. Whereas adipogenic genes are released from LADs, LADs sequester downregulated or repressed genes irrelevant for the adipose lineage. However, LAD repositioning only partly concurs with gene expression changes. Differentially expressed genes in LADs, including LADs conserved throughout differentiation, reside in local euchromatic and lamin-depleted sub-domains. In these sub-domains, pre-differentiation histone modification profiles correlate with the LAD versus inter-LAD outcome of these genes during adipogenic commitment. Lastly, we link differentially expressed genes in LADs to short-range enhancers which overall co-partition with these genes in LADs versus inter-LADs during differentiation. We conclude that LADs are predictable structural features of adipose nuclear architecture that restrain non-adipogenic genes in a repressive environment.


Choroidal neovascularization enhanced by Chlamydia pneumoniae via Toll-like receptor 2 in the retinal pigment epithelium.
Choroidal neovascularization (CNV) is directly related to visual loss in persons with age-related macular degeneration (AMD) and other macular disorders. Chlamydia pneumoniae, a prokaryotic pathogen that causes chronic inflammation, is recognized as a risk factor for cardiovascular diseases. In this study, the authors investigated the association between C. pneumoniae infection and AMD using a laser-induced CNV model in mice. C57BL/6 mice, myeloid differentiation factor (MyD) 88 knockout (KO) mice, Toll-like receptor (TLR) 2 KO mice, and TLR4 KO mice were used. Experimental CNV was induced by rupturing the Bruch's membrane by laser photocoagulation (PC). Seven days after PC, the eyes were enucleated and the areas of CNV were measured in choroidal flat mounts. Cytokine gene expression by quantitative real-time PCR in the primary cultured retinal pigment epithelium (RPE) cells was also examined. Vitreous injection of the C. pneumoniae antigen increased the size of CNV. Although lipopolysaccharide stimulation can induce multiple cytokines, cultured mouse RPE cells from C57BL/6 mice expressed IL-6 and VEGF, but not TNF-alpha mRNA, in response to C. pneumoniae antigen. RPE cells from either MyD88 KO mice or TLR2 KO mice did not respond to the C. pneumoniae antigen. TLR2 KO mice did not augment the size increase of experimental CNV by C. pneumoniae antigen in vivo. C. pneumoniae can trigger inflammatory responses in the eye and promote experimental CNV in a TLR2-dependent manner. These data provide experimental evidence to imply persistent C. pneumoniae infection is a risk factor for AMD.


Estimating species - area relationships by modeling abundance and frequency subject to incomplete sampling.
Models and data used to describe species-area relationships confound sampling with ecological process as they fail to acknowledge that estimates of species richness arise due to sampling. This compromises our ability to make ecological inferences from and about species-area relationships. We develop and illustrate hierarchical community models of abundance and frequency to estimate species richness. The models we propose separate sampling from ecological processes by explicitly accounting for the fact that sampled patches are seldom completely covered by sampling plots and that individuals present in the sampling plots are imperfectly detected. We propose a multispecies abundance model in which community assembly is treated as the summation of an ensemble of species-level Poisson processes and estimate patch-level species richness as a derived parameter. We use sampling process models appropriate for specific survey methods. We propose a multispecies frequency model that treats the number of plots in which a species occurs as a binomial process. We illustrate these models using data collected in surveys of early-successional bird species and plants in young forest plantation patches. Results indicate that only mature forest plant species deviated from the constant density hypothesis, but the null model suggested that the deviations were too small to alter the form of species-area relationships. Nevertheless, results from simulations clearly show that the aggregate pattern of individual species density-area relationships and occurrence probability-area relationships can alter the form of species-area relationships. The plant community model estimated that only half of the species present in the regional species pool were encountered during the survey. The modeling framework we propose explicitly accounts for sampling processes so that ecological processes can be examined free of sampling artefacts. Our modeling approach is extensible and could be applied to a variety of study designs and allows the inclusion of additional environmental covariates.


Plants from disturbed savannah vegetation and their usage by Bakongo tribes in Uíge, Northern Angola.
This study represents the first in-depth ethnobotanical study in the province of Uíge in northern Angola and documents the traditional knowledge of the Bakongo people living in the area. Due to deforestation and frequent fires, degraded savannahs dominate the landscape in the study region. Here we provide a list of useful plants from these savannahs including quantitative data about cultural importance of the respective species, aiming on the one hand to conserve the local knowledge and on the other hand to create a reliable basis for research projects in the region. Field work was conducted in April and May 2014 in 5 municipalities of Uíge province. The study is based on 32 semi-structured and free-listing interviews, group discussions of varying scope and 14 field trips, involving a total of 82 informants. Throughout the course of the study herbarium specimens of the useful species were collected for later identification. Cultural importance index was applied to analyse the data sets recorded and to determine the best-known useful species in the region. All data sets were compared to the literature available for the region. The study documents a total of 498 citations for the use of 122 plants from 48 families, 34.0 % of which were unknown according to the literature used for comparison. The high amount (71 %) of medical use-reports indicates that plants still play a crucial role in rural health care. We identified 14 plant species of special interest for pharmacological analysis. Species of highest cultural importance are Annona senegalensis Pers. and Sarcocephalus latifolius (Sm.) E.A., both of which are frequently found in disturbed savannahs. The study points out the importance of savannahs even if degraded in terms of useful plants and provides a valuable addition to current knowledge of plant use in Northern Angola. This is not only essential for further studies, i.e. regarding pharmaceutical agents, but also for the design of a planned botanical garden of the University Kimpa Vita in Uíge, which aims at communicating the findings to the local people.


[Can an online risk assessment tool for identification of hereditary colorectal cancer reach the at-risk population and influence screening compliance?].
Lynch syndrome is a frequent autosomal dominant cancer predisposition leading to an estimated incidence of 3000-4000 new cancer diagnoses of colorectal and endometrial cancer in Germany per year. The underlying hereditary condition is largely underestimated and underrecognized by physicians. The usually young at-risk population, feeling insecure about their personal risk assessment, seeks information online. The aim of this study was to evaluate whether this online risk assessment tool for identification of increased risk for hereditary cancer predisposition reaches the target population and whether it succeeds in positively influencing intensified screening compliance. The underlying algorithm for the test is based on the Bethesda and Amsterdam criteria and recent literature on polyposis syndromes. In the context of interrogating family and personal history, a total of five risk categories were defined. In addition to the cancers as defined in the above mentioned criteria, precursor lesions (polyps) were integrated into the risk estimate. Prior to launching, the algorithm was validated in family pedigrees of 102 mutation carriers with identified MLH-1 or MSH-2 mutations. During the time interval analysed, which was between October 2008 and April 2011 a total of 656 participants were included. Among these 19.1 % (125/656) belonged to the target population at increased familial or hereditary risk. 72.8 % (91/125) were yet healthy with known cancer-affected relatives. Merely 34.4 % (11/32) of the high-risk population were currently participating in a risk adjusted screening program. After completion of the online test 62.5 % (20/32) felt motivated to reconsider and adjust accordingly with increased surveillance. The test received an overall "good" evaluation (83 %) based on handling, performance and information content. This online risk-assessment tool was mainly completed by healthy (not cancer-affected) individuals with an increased risk for familial or hereditary colorectal cancer predisposition. The family pedigrees were comparable to these of known mutation carriers. The at-risk population was positively motivated to intensify screening strategies and the test received an overall positive evaluation.


A sweet cycle for Arabidopsis G-proteins: Recent discoveries and controversies in plant G-protein signal transduction.
Heterotrimeric G-proteins are a class of signal transduction proteins highly conserved throughout evolution that serve as dynamic molecular switches regulating the intracellular communication initiated by extracellular signals including sensory information. This property is achieved by a guanine nucleotide cycle wherein the inactive, signaling-incompetent Galpha subunit is normally bound to GDP; activation to signaling-competent Galpha occurs through the exchange of GDP for GTP (typically catalyzed via seven-transmembrane domain G-protein coupled receptors [GPCRs]), which dissociates the Gbetagamma dimer from Galpha-GTP and initiates signal transduction. The hydrolysis of GTP, greatly accelerated by "Regulator of G-protein Signaling" (RGS) proteins, returns Galpha to its inactive GDP-bound form and terminates signaling. Through extensive characterization of mammalian Galpha isoforms, the rate-limiting step in this cycle is currently considered to be the GDP/GTP exchange rate, which can be orders of magnitude slower than the GTP hydrolysis rate. However, we have recently demonstrated that, in Arabidopsis, the guanine nucleotide cycle appears to be limited by the rate of GTP hydrolysis rather than nucleotide exchange. This finding has important implications for the mechanism of sugar sensing in Arabidopsis. We also discuss these data on Arabidopsis G-protein nucleotide cycling in relation to recent reports of putative plant GPCRs and heterotrimeric G-protein effectors in Arabidopsis.


Comment on "A vestige of Earth's oldest ophiolite".
The claim by Furnes et al. (Reports, 23 March 2007, p. 1704) that Greenland metavolcanic rocks require Paleoarchean sea-floor spreading is incompatible with their own data. The purported sheeted dikes have the composition of pyroxenitic komatiite and could not have fed the adjacent ferroandesitic pillow lavas. Neither type has ophiolitic analogs, and both are likely ensialic.


[A fatal infection due to avian influenza-A (H7N7) virus and adjustment of the preventive measures].
In February 2003, the highly pathogenic avian influenza-A virus, subtype H7N7, was the causative agent of a large outbreak of fowl plague in the Netherlands. Two days after visiting a poultry farm that was infected by fowl plague, a 57-year-old male veterinarian developed malaise, headache and fever. After 8 days he was admitted to hospital with signs of pneumonia. Five days later, his condition deteriorated alarmingly. Despite extensive pharmacotherapy he died 4 days later of acute pneumonia. Influenza-A virus, subtype H7N7, was identified by means of reverse transcriptase/PCR in broncho-alveolar washings that had been obtained earlier; routine virus culture yielded the isolate A/Nederland/219/03, which differs by 14 amino-acid substitutions from the first isolate in a chicken (A/kip/Nederland/1/03). Partly as a result of this case, the preventive measures were then adjusted; people who came into contact with infected poultry were given increased possibilities for vaccination and the administration of oseltamivir.


Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study.
Eradication of hepatitis C virus (HCV) infection via interferon-based treatment lowers hepatocellular carcinoma risk; some research suggests this effect extends to interferon-free treatment. The objective of this retrospective cohort study was to examine the association of direct-acting antiviral (DAA) exposure with risk of incident liver cancer in real-world data. From United States administrative claims data through March 31, 2017, we identified 30 183 adult HCV patients exposed to DAAs. For comparison, we identified contemporary adult HCV patients without evidence of HCV treatment (N = 137 502), and historical HCV patients treated with interferon prior to the introduction of DAAs (N = 12 948). Included patients had at least 12 months of prior enrolment and no evidence of prior liver cancer at baseline. Hazard ratios (HRs) estimating risk of incident liver cancer associated with DAA treatment were calculated using Cox proportional hazards methods. Relative to untreated HCV patients, DAA-treated patients were older, more likely to be male, and more likely to have cirrhosis at baseline. After adjustment, DAA treatment was associated with a significantly reduced risk of liver cancer relative to no treatment (adjusted HR = 0.84, 95% CI: 0.73-0.96), and relative to interferon-based treatment in the pre-DAA era (HR = 0.69, 95% CI: 0.59-0.81). In this large, population-based study, DAA-based treatment was associated with a reduced risk of incident liver cancer relative to both no HCV treatment and to interferon-based treatment in the pre-DAA era. As additional follow-up time of DAA-treated patients accrues, we anticipate that the long-term benefits of DAA treatment will become more apparent.


The diagnostic challenge of primary dystonia: evidence from misdiagnosis.
Although the understanding of dystonia has improved in recent years, primary dystonia is still insufficiently recognized and patients may not receive the correct diagnosis, leading to transient or permanent misclassification of their symptoms. We reviewed cases of primary dystonia who were at first misdiagnosed and analyzed the reasons why the correct diagnosis was first missed and later retained. Primary dystonia is misdiagnosed mainly, but not exclusively, in favor of other movement disorders: Parkinson's disease (PD), essential tremor, myoclonus, tics, psychogenic movement disorder (PMD), and even headache or scoliosis. Accounts are more numerous for PD and PMD, where diagnostic tests, such as DAT scan and psychological assessment, support clinical orientation. The correct diagnosis was achieved in all cases following the recognition of inconsistencies in the first judgment and of distinctive clinical features of dystonia. These clues have been collected here and assembled into a diagnostic epitome.


Milking behaviour of buffalo cows: entrance order and side preference in the milking parlour.
On two farms, three milking groups of buffalo cows were used to assess the consistency of entrance order and the preference for one side of the milking parlour. On Farm 1 (F1) all animals were primiparous (n=57). On Farm 2, three primiparous, 16 secondiparous and 36 multiparous cows (range 1-8) constituted group F2G1; whereas group F2G2 had 12 primiparous, 10 secondiparous and 14 multiparous cows (range 1-10). Animals were milked in auto-tandem milking parlours (2×5 and 2×6 for Farms 1 and 2, respectively). For each cow, entrance order into milking parlour, side where she was milked, milk yield, time and duration of milking were recorded. These data were derived from the computerised identification of cows. The sequence in which the cows entered the milking parlour ranged from 1 to 57 for group F1, from 1 to 55 for group F2G1 and from 1 to 36 for group F2G2. The analysis of data was conducted on 130, 120 and 92 consecutive milkings for groups F1, F2G1 and F2G2, respectively. Kendall's coefficients of concordance showed a strong constancy of the entrance order into milking parlour for groups F1 (W=0·658; χ2=4792·81; P<0·001), F2G1 (W=0·779; χ2=5046·81; P<0·001) and F2G2 (W=0·624; χ2=2030·48; P<0·001). Spearman rank correlation coefficients indicated that the more productive cows in groups F1 and F2G1 tended to enter the milking parlour first (r s=-0·221 and r s=-0·215; P<0·10; respectively). In group F2G1, a negative correlation was found between duration of milking and order of entry in the milking parlour (r s=-0·265; P<0·05). Animals in group F2G2 (r s=0·334; P<0·05) with higher days in milk entered the milking parlour latterly. In all three groups, 68 cows (45·9%) preferred the right side of the milking parlour, 73 the left side (49·3%) and the remaining seven (4·8%) showed no preference. Finally, negative correlations were found between mean entrance order and parity for both groups of Farm 2 (r s=-0·319; P<0·05 and r s=-0·325; P<0·05 for F2G1 and F2G2, respectively). As buffaloes showed higher entrance order consistency and side preference than other domestic ruminants, it is concluded that management practices that disturb their choice should be avoided in order to minimise stress during farming routines.


The African diaspora: mitochondrial DNA and the Atlantic slave trade.
Between the 15th and 19th centuries ad, the Atlantic slave trade resulted in the forced movement of approximately 13 million people from Africa, mainly to the Americas. Only approximately 11 million survived the passage, and many more died in the early years of captivity. We have studied 481 mitochondrial DNAs (mtDNAs) of recent African ancestry in the Americas and in Eurasia, in an attempt to trace them back to particular regions of Africa. Our results show that mtDNAs in America and Eurasia can, in many cases, be traced to broad geographical regions within Africa, largely in accordance with historical evidence, and raise the possibility that a greater resolution may be possible in the future. However, they also indicate that, at least for the moment, considerable caution is warranted when assessing claims to be able to trace the ancestry of particular lineages to a particular locality within modern-day Africa.


The diversity and plasticity of adult hepatic progenitor cells and their niche.
The liver is a unique organ for homoeostasis with regenerative capacities. Hepatocytes possess a remarkable capacity to proliferate upon injury; however, in more severe scenarios liver regeneration is believed to arise from at least one, if not several facultative hepatic progenitor cell compartments. Newly identified pericentral stem/progenitor cells residing around the central vein is responsible for maintaining hepatocyte homoeostasis in the uninjured liver. In addition, hepatic progenitor cells have been reported to contribute to liver fibrosis and cancers. What drives liver homoeostasis, regeneration and diseases is determined by the physiological and pathological conditions, and especially the hepatic progenitor cell niches which influence the fate of hepatic progenitor cells. The hepatic progenitor cell niches are special microenvironments consisting of different cell types, releasing growth factors and cytokines and receiving signals, as well as the extracellular matrix (ECM) scaffold. The hepatic progenitor cell niches maintain and regulate stem cells to ensure organ homoeostasis and regeneration. In recent studies, more evidence has been shown that hepatic cells such as hepatocytes, cholangiocytes or myofibroblasts can be induced to be oval cell-like state through transitions under some circumstance, those transitional cell types as potential liver-resident progenitor cells play important roles in liver pathophysiology. In this review, we describe and update recent advances in the diversity and plasticity of hepatic progenitor cell and their niches and discuss evidence supporting their roles in liver homoeostasis, regeneration, fibrosis and cancers.


Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias.
MEN1 is a syndrome of parathyroid adenomas, gastrinomas, prolactinomas, and other endocrine tumors. Collagenomas and facial angiofibromas are newly recognized but common skin expressions. Many tumors in MEN1 are benign; however, many entero-pancreatic neuroendocrine tumors and foregut carcinoid tumors are malignant. MEN1 is thus the expression of a cancer gene but without available prevention or cure for malignancy. Hereditary (as compared to sporadic) endocrine tumors show early onset age and multiplicity, because each cell of the body has "one hit" by inheritance. Multiple neoplasia syndromes with endocrine tumor(s) all include nonendocrine components; their known defective genes seem mainly to disturb cell accumulation. Hereditary neoplasia/hyperplasia of one endocrine tissue reflects a defect that is tissue selective and directed at cell secretion. Though the hereditary endocrine neoplasias are rare, most of their identified genes also contribute to common sporadic endocrine neoplasms. Hereditary tumors may be caused by activation of an oncogene (e.g., RET) or, more often, by inactivation of a tumor suppressor gene (e.g., P53, MEN1). Recently, MEN1 was identified by positional cloning. This strategy included narrowing the gene candidate interval, identifying many or all genes in that interval, and testing the newly identified candidate genes for mutation in MEN1 cases. MEN1 was identified because it showed mutation in 14 of 15 MEN1 cases. NIH testing showed germline MEN1 mutations in 47 of 50 MEN1 index cases and in seven of eight cases with sporadic MEN1. Despite proven capacity to find germline MEN1 mutation, NIH testing found no MEN1 mutation among five families with isolated hyperparathyroidism, suggesting that this often arises from mutation of other gene(s). Analogous studies in Japan found that familial isolated pituitary tumors also did not show MEN1 germline mutation. MEN1 mutation testing can now be considered for cases of MEN1 and its phenocopies and for asymptomatic members of families with known MEN1 mutation. Germline MEN1 testing does not have the urgency of RET testing in MEN2a and 2b, as MEN1 testing does not commonly lead to an important intervention. Somatic MEN1 mutation was found in sporadic tumors: parathyroid adenoma (21%), gastrinoma (33%), insulinoma (17%), and bronchial carcinoid (36%). For each of these, MEN1 was the known gene most frequently mutated. MEN1 has a widely expressed mRNA that encodes a protein (menin) of 610 amino acids. The protein sequence is not informative about domains or functions. The protein was mainly nuclear. Menin binds to JunD, an AP-1 transcription factor, inhibiting JunD's activation of transcription. Most of the germline and somatic MEN1 mutations predict truncation of menin, a likely destructive change. Inactivating MEN1 mutations in germline and in sporadic neoplasms support prior predictions that MEN1 is a tumor suppressor gene. Germline MEN1 mutation underlies all or most cases of MEN1 (familial or sporadic). Somatic MEN1 mutation is the most common gene mutation in many sporadic endocrine tumor types.


Focal laser ablation for localized prostate cancer.
Throughout history, medicine has witnessed paradigm shifts that significantly change patient treatment. In surgical oncology, the introduction of lumpectomy revolutionized breast cancer treatment while partial nephrectomy has altered the management of kidney cancer. In both cases, organ preservation is combined with efficacious management of the cancer via a less invasive approach. Within urology, prostate cancer (PCa) may be the next to benefit from such a treatment paradigm. Current management of PCa involves either whole organ treatment, with the inherent side effects, while selected patients are eligible for active surveillance. Focal therapy offers a middle ground for low-risk patients with PCa, again using the principles of a minimally invasive treatment of the cancer, in this case using an energy source with few side effects, combined with maximal organ preservation. Because focal therapy for PCa is still in evolution, there is no consensus on the ideal energy source that should be used to ablate the PCa, imaging to monitor the tissue destruction in real time, how many treatments may be offered, and the ideal follow-up regimen. Long-term follow-up of patients is needed before it is recommended as a first-line treatment. Nevertheless, evidence is accumulating that radically treating PCa holds survival benefit for patients; however, the number of men needed to treat is considerable, with significant side effects; thus, more centers are investigating focal therapy as an option. This review focuses on the use of the laser as the energy source for focal ablation, while bringing historically relevant information regarding laser energy and highlighting the perceived advantageous of focal laser ablation.


Structural Heteropatriarchy and Birth Outcomes in the United States.
Emerging evidence links structural sexism and structural discrimination against lesbian, gay, and bisexual (LGB) populations to poor health outcomes, but studies have yet to examine the combined effects of these mutually reinforcing systems of inequality. Therefore, we developed a composite measure of structural heteropatriarchy-which includes state-level LGB policies, family planning policies, and indicators of structural sexism (e.g., women's political and economic position relative to men)-and examined its relationship to birth outcomes using data from Waves I to V of the National Longitudinal Study of Adolescent to Adult Health. Multivariate regression analyses demonstrated that higher levels of heteropatriarchy were associated with an increased risk of preterm birth and decreased birth weight, net of important covariates. There was no association between clinical low birth weight and heteropatriarchy, or interactions between heteropatriarchy and individuals' race, ethnicity or sexual identity, suggesting a negative effect of heteropatriarchy on birth outcomes for all pregnant people. This study demonstrates the importance of considering gender and sexuality as mutually reinforcing systems of oppression that impact population health. Future research should examine the impact of heteropatriarchy on additional health outcomes and in conjunction with other structural inequalities such as racism and transgender oppression.


Involvement of oxidative stress in occurrence of relapses in multiple sclerosis: the spectrum of oxidatively modified serum proteins detected by proteomics and redox proteomics analysis.
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system. Several evidences suggest that MS can be considered a multi-factorial disease in which both genetics and environmental factors are involved. Among proposed candidates, growing results support the involvement of oxidative stress (OS) in MS pathology. The aim of this study was to investigate the role of OS in event of exacerbations in MS on serum of relapsing-remitting (RR-MS) patients, either in relapsing or remitting phase, with respect to serum from healthy subjects. We applied proteomics and redox proteomics approaches to identify differently expressed and oxidatively modified proteins in the low-abundant serum protein fraction. Among differently expressed proteins ceruloplasmin, antithrombin III, clusterin, apolipoprotein E, and complement C3, were up-regulated in MS patients compared with healthy controls. Further by redox proteomics, vitamin D-binding protein showed a progressive trend of oxidation from remission to relapse, respect with controls. Similarly, the increase of oxidation of apolipoprotein A-IV confirmed that levels of OS are elevated with the progression of the disease. Our findings support the involvement of OS in MS and suggest that dysfunction of target proteins occurs upon oxidative damage and correlates with the pathology.


Empirical reproducibility, sensitivity, and optimization of acquisition protocol, for Neurite Orientation Dispersion and Density Imaging using AMICO.
Neurite Orientation Dispersion and Density Imaging (NODDI) has been gaining prominence for estimating multiple diffusion compartments from MRI data acquired in a clinically feasible time. To establish a pathway for adoption of NODDI in clinical studies, it is important to understand the sensitivity and reproducibility of NODDI metrics on empirical data in the context of acquisition protocol and brain anatomy. Previous studies addressed reproducibility across the 3 T scanners and within session and between subject reproducibility at 1.5 T and 3 T. However, empirical reproducibility on the performance of NODDI metrics based on b-value and diffusion-sensitized directions has not yet been addressed. In this study, we investigate a high angular resolution dataset with 11 repeats of a study with five b-values shells (1000, 1500, 2000, 2500 and 3000 s/mm2) and 96 directions per shell on a single subject. We validated the findings with a dataset from second subject with 10 repeats and 3 b-value shells (1000, 2000, 3000 s/mm2). The NODDI model was estimated using Accelerated Microstructure Imaging via Convex Optimization (AMICO) for different b-values and gradient directions on two-shell High Angular Resolution Density Imaging (HARDI) data fixing the lower shell at b = 1000 s/mm2. NODDI model applied to all acquired imaging data was used as a baseline gold standard for comparison. Additionally, we characterize orientation dispersion index (ODI) reproducibility using single-shell data. The experimental findings confirmed the sensitivity of intracellular volume fraction (Vic) with the choice of outer shell b-value more than with the choice of gradient directions. On the other hand, ODI is more sensitive to the number of gradient directions compared to b-value selection. Single-shell results for ODI are more comparable to 2-shell data at lower b-values than higher b-values. Recommended settings by region of interest and acquisition time are reported for the researchers considering using NODDI in human studies and/or comparing results across acquisition protocols.


Topical treatments for fungal infections of the skin and nails of the foot.
Fungal infections of the feet normally occur in the outermost layer of the skin (epidermis). The skin between the toes is a frequent site of infection which can cause pain and itchiness. Fungal infections of the nail (onychomycosis) can affect the entire nail plate. To assess the effects of topical treatments in successfully treating (rate of treatment failure) fungal infections of the skin of the feet and toenails and in preventing recurrence. We searched the Cochrane Skin Group Specialised Register (January 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE and EMBASE (from inception to January 2005). We screened the Science Citation Index, BIOSIS, CAB - Health and Healthstar, CINAHL DARE, NHS Economic Evaluation Database and EconLit (March 2005). Bibliographies were searched. Randomised controlled trials (RCTs) using participants who had mycologically diagnosed fungal infections of the skin and nails of the foot. Two authors independently summarised the included trials and appraised their quality of reporting using a structured data extraction tool. Of the 144 identified papers, 67 trials met the inclusion criteria. Placebo-controlled trials yielded the following pooled risk ratios (RR) of treatment failure for skin infections: allylamines RR 0.33 (95% CI 0.24 to 0.44); azoles RR 0.30 (95% CI 0.20 to 0.45); ciclopiroxolamine RR 0.27 (95% CI 0.11 to 0.66); tolnaftate RR 0.19 (95% CI 0.08 to 0.44); butenafine RR 0.33 (95% CI 0.24 to 0.45); undecanoates RR 0.29 (95% CI 0.12 - 0.70). Meta-analysis of 11 trials comparing allylamines and azoles showed a risk ratio of treatment failure RR 0.63 (95% CI 0.42 to 0.94) in favour of allylamines. Evidence for the management of topical treatments for infections of the toenails is sparser. There is some evidence that ciclopiroxolamine and butenafine are both effective but they both need to be applied daily for prolonged periods (at least 1 year). The 6 trials of nail infections provided evidence that topical ciclopiroxolamine has poor cure rates and that amorolfine might be substantially more effective but more research is required. Placebo-controlled trials of allylamines and azoles for athlete's foot consistently produce much higher percentages of cure than placebo. Allylamines cure slightly more infections than azoles and are now available OTC. Further research into the effectiveness of antifungal agents for nail infections is required.


The utility of tympanic versus oral temperature measurements of firefighters in emergency incident rehabilitation operations.
Emergency incident rehabilitation (EIR) is the process by which firefighters receive medical screening and monitoring as well as oral rehydration while on the scene of intense or extended fire or rescue operations. A crucial parameter in EIR medical monitoring is temperature determination because heat-related illnesses are common. The objective of this study was to compare the use of oral temperature versus infrared tympanic temperature determinations of firefighters in the outdoor environment of EIR operations. This was a prospective observational study of firefighters participating in training scenarios involving heavy smoke and fire conditions at municipal fire training facilities. Outdoor temperature and relative humidity were obtained for each training session. Subjects were outfitted fully for fire fighting duties including full protective clothing and self-contained breathing apparatus (SCBA). Immediately on exiting the fire building, firefighters removed their SCBA masks, protective hoods, and helmets, and had simultaneous oral and tympanic temperatures taken (time 0). The subjects then sat outdoors for 10 minutes and their temperatures were again obtained (time 10). Oral and tympanic temperatures for both time points were calculated as means +/- SD. An intraclass correlation coefficient was calculated to determine how closely the simultaneously obtained oral and tympanic temperatures determinations at T-0 and T-10 correlated with each other. Forty-two firefighters (mean age, 44.6 years; SD 9.6) were enrolled during four separate training days. There was poor correlation between oral and tympanic temperatures in firefighters both at time 0 (r = 0.10) and at time 10 (r = 0.18). There is poor correlation between tympanic and oral temperature determinations in the EIR setting. Oral temperature determinations may be preferable to tympanic temperature determination in the EIR setting.


Breastfeeding training improves health worker performance in rural Nigeria.
The training of health workers in breastfeeding and lactation management is to enable them make correct breastfeeding recommendations to mothers. This study aims to provide answers to two research questions: what components of breastfeeding training are easily achieved with extension health workers, and what health worker variables affect these outcomes. Multivariable analysis of the outcomes of a controlled breastfeeding training programme for community health workers (CHW) in rural communities of Osun State, Nigeria, was performed by logistic regression. The results show that the training was the most powerful predictor of correct CHW recommendations on breastfeeding (OR = 60.25, p-0.0000), and of 'perfect' breastfeeding knowledge (OR = 192.49, p = 0.0000). Younger CHWs (in the age bracket 20 to 29 years) were significantly more likely to make correct recommendations on exclusive breastfeeding (OR = 3.02, p = 0.0304). Other CHW variables such as sex, experience, job status, and marital status did not make consistently significant independent contributions to the outcomes. The results suggest that breastfeeding education can enhance CHW professional recommendations on breastfeeding and should be extended to all categories of health workers.


A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis.
Polymorphonuclear leukocytes (PMN) achieve an intermediate or primed state of activation following stimulation with certain agonists. Primed PMN have enhanced responsiveness to subsequent stimuli, which can be beneficial in eliminating microbes but may cause host tissue damage in certain disease contexts, including sepsis. As PMN priming by TLR4 agonists is well described, we hypothesized that ligation of TLR2/1 or TLR2/6 would prime PMN. Surprisingly, PMN from only a subset of donors were primed in response to the TLR2/1 agonist, Pam3CSK4, although PMN from all donors were primed by the TLR2/6 agonist, FSL-1. Priming responses included generation of intracellular and extracellular reactive oxygen species, MAPK phosphorylation, integrin activation, secondary granule exocytosis, and cytokine secretion. Genotyping studies revealed that PMN responsiveness to Pam3CSK4 was enhanced by a common single-nucleotide polymorphism (SNP) in TLR1 (rs5743618). Notably, PMN from donors with the SNP had higher surface levels of TLR1 and were demonstrated to have enhanced association of TLR1 with the endoplasmic reticulum chaperone gp96. We analyzed TLR1 genotypes in a pediatric sepsis database and found that patients with sepsis or septic shock who had a positive blood culture and were homozygous for the SNP associated with neutrophil priming had prolonged pediatric intensive care unit length of stay. We conclude that this TLR1 SNP leads to excessive PMN priming in response to cell stimulation. Based on our finding that septic children with this SNP had longer pediatric intensive care unit stays, we speculate that this SNP results in hyperinflammation in diseases such as sepsis.


Participation in modified sports programs: a longitudinal study of children's transition to club sport competition.
Many children are not physically active enough for a health benefit. One avenue of physical activity is modified sport programs, designed as an introduction to sport for young children. This longitudinal study identified trends in participation among children aged 4-12 years. Outcomes included continuation in the modified sports program, withdrawal from the program or transition to club sport competition. De-identified data on participant membership registrations in three popular sports in the Australian state of Victoria were obtained from each sport's state governing body over a 4-year period (2009-2012 for Sport A and 2010-2013 for Sports B and C). From the membership registrations, those who were enrolled in a modified sports program in the first year were tracked over the subsequent three years and classified as one of: transition (member transitioned from a modified sport program to a club competition); continue (member continued participation in a modified sport program; or withdraw (member discontinued a modified program and did not transition to club competition). Many modified sports participants were very young, especially males aged 4-6 years. More children withdrew from their modified sport program rather than transitioning. There were age differences between when boys and girls started, withdrew and transitioned from the modified sports programs. If we can retain children in sport it is likely to be beneficial for their health. This study highlights considerations for the development and implementation of sport policies and programming to ensure lifelong participation is encouraged for both males and females.


Abnormalities in extracellular glycine and glutamate levels in the striatum of sandy mice.
Glycine regulates glutamatergic neurotransmission, and several papers have reported the relationship between glycine and schizophrenia. The dysbindin-1 (DTNBP1: dystrobrevin-binding protein 1) gene is related to glutamatergic neurotransmission and has been found to be a strong candidate gene for schizophrenia. In this study, we clarified the relationship between dysbindin, glutamate, and glycine with in vivo microdialysis methods. We measured extracellular glycine and glutamate levels in the striatum of sandy (sdy) mice using in vivo microdialysis methods. Sdy mice express no dysbindin protein owing to a deletion in the dysbindin-1 gene. In addition, we measured changes in those amino acids after methamphetamine (METH) administration. The basal levels of extracellular glycine and glutamate in the striatum of sdy mice were elevated. These extracellular glutamate levels decreased gradually after METH administration and were not subsequently different from those of wild-type mice. These results suggest that dysbindin might modulate glycine and glutamate release in vivo.


Postfire stand structure in a semiarid savanna: cross-scale challenges estimating biomass.
Algorithms relating remotely sensed woody cover to biomass are often the basis for large-scale inventories of aboveground carbon stocks. However, these algorithms are commonly applied in a generic fashion without consideration of disturbances that might alter vegetation structure. We compared field and remote sensing estimates of woody biomass on savannas with contrasting disturbance (fire) histories and assessed potential errors in estimating woody biomass from cover without considering fire history. Field surveys quantified multilayer cover (MLC) of woody and succulent plants on sites experiencing wildfire in 1989 or 1994 and on nearby unburned (control) sites. Remote sensing estimates of the woody cover fraction (WCF) on burned and control sites were derived from contemporary (2005) dry-season Landsat Thematic Mapper imagery (during a period when herbaceous cover was senescent) using a probabilistic spectral mixture analysis model. Satellite WCF estimates were compared to field MLC assessments and related to aboveground biomass using allometry. Field-based MLC and remotely sensed WCFs both indicated that woody cover was comparable on control areas and areas burned 11-16 years ago. However, biomass was approximately twofold higher on control sites. Canopy cover was a strong predictor of woody biomass on burned and control areas, but fire history significantly altered the linear cover-biomass relationship on control plots to a curvilinear relationship on burned plots. Results suggest predictions of woody biomass from "generic" two-dimensional (2-D) cover algorithms may underestimate biomass in undisturbed stands and overestimate biomass in stands recovering from disturbance. Improving the accuracy of woody-biomass estimates from field and/or remotely sensed cover may therefore require disturbance-specific models or detection of vegetation height and transforming 2-D vegetation cover to 3-D vegetation volume.


The power of information and contraceptive choice in a family planning setting in Mexico.
This study measured the effect of information about family planning methods and STD risk factors and prevention, together with personal choice on the selection of intrauterine devices (IUDs) by clients with cervical infection. We conducted a randomised, controlled trial in which family planning clients were assigned to one of two groups, the standard practice (control) group in which the provider selected the woman's contraceptive and the information and choice (intervention) group. The study enrolled 2107 clients in a family planning clinic in Mexico City. Only 2.1% of the clients had gonorrhoea or chlamydial infections. Significantly fewer women in the intervention group selected the IUD than the proportion for whom the IUD was recommended in the standard care group by clinicians (58.2% v 88.2%, p = 0.0000). The difference was even more pronounced among infected women: 47.8% v 93.2% (intervention v control group, p = 0.0006). The intervention increased the selection of condoms and reduced the selection of IUDs, especially among women with cervical infections, for whom IUD insertion is contraindicated.


Doxorubicin chemomyectomy is enhanced when performed two days following bupivacaine injections: the effect coincides with the peak of muscle satellite cell division.
Doxorubicin is effective in permanently removing muscle after direct injection into the eyelid for treatment of blepharospasm and hemifacial spasm. However, patients often require two or more injection series before full abatement of their spasms is achieved. Local anesthetics cause muscle necrosis, followed by regeneration, a process that requires activation and division of muscle satellite cells. This study examined whether the muscle toxicity of doxorubicin could be amplified by injection of doxorubicin into the eyelid of rabbits 2 days after a local anesthetic injury, perhaps exploiting the toxic effects of doxoribicin on satellite cells at the peak time of their division after injury. Rabbit eyelids received two series of injections of bupivacaine and hyaluronidase spaced 18 hours apart. Two days later, the eyelids were injected with either 0.5 or 1 mg doxorubicin. Animals were monitored daily for onset and duration of skin injury. After 1 month, the eyelids were assessed for muscle loss using histologic and morphometric techniques. Injection of doxorubicin during the peak of satellite cell activation and division 2 days after injury significantly increased muscle loss over doxorubicin alone. This treatment did not result in increased skin injury compared with doxorubicin alone. Permanent muscle loss was increased when doxorubicin was injected at the peak of satellite cell division 2 days after injury of the muscle with bupivacaine in rabbit eyelid, taking advantage of the antimitotic effects of doxorubicin on satellite cell division during the period of active regeneration. When local anesthetic injection immediately preceded the doxorubicin injection, increased myotoxicity was not seen. The injection of doxorubicin into muscle 2 days after a previous injury maximizes muscle loss. The increased muscle loss provided by this double treatment may decrease the number of injection visits required by blepharospasm and hemifacial spasm patients during their course of treatment, thus reducing the number of patients with side effects, which increases with repeated exposures of the eyelid to doxorubicin.


[Celiac disease and malocclusion].
Celiac disease is an autoimmune disease, caused by a permanent intolerance to gluten, that occurs in genetically predisposed individuals. It causes enteropathy. In these individuals a prolonged exposure to gluten increases the risk of developing other pathologies, which may affect both developing dentition and oral mucosa. Clinical presentations are various and atypical. Celiac patients may have enamel hypoplasia, higher prevalence of dental caries, delayed eruption of teeth and lower jaw growth. These factors predispose to malocclusion.


Structure of the feline c-fes/fps proto-oncogene: genesis of a retroviral oncogene.
The nucleotide sequence of the feline c-fes/fps proto-oncogene was analyzed. Comparison with v-fes and v-fps revealed that all v-fes/fps homologous sequences were dispersed over 11 kilobase pairs in 19 interspersed segments. All segments, numbered exon 1 to exon 19 as in the chicken and human loci, were flanked by consensus splice junctions. The putative promoter region contained a CATT sequence and three CCGCCC motifs which were also found in the human locus at similar positions. About 200 nucleotides downstream of a translational stop codon in exon 19, a putative poly(A) addition signal was identified. Using the putative translation initiation codon in exon 2, a 93,000-molecular-weight protein could be deduced. This protein resembled very well the putative protein of the human c-fes/fps proto-oncogene (94% overall homology) and, although less well, the putative protein of the chicken c-fes/fps proto-oncogene (70% overall homology). As far as the feline c-fes/fps proto-oncogene sequences transduced to the Gardner-Arnstein (GA) and Snyder-Theilen (ST) strains of feline sarcoma virus (FeSV) are concerned, homology in deduced amino acid sequences between the GA- and ST-v-fes viral oncogenes and the proto-oncogene was 99%. Analysis of the recombination junctions between feline leukemia virus and v-fes sequences in GA- and ST-FeSV proviral DNA revealed for the left-hand junction the involvement of homologous recombination, presumably at the DNA level. The right-hand junction, which appeared identical in the GA-FeSV and ST-FeSV genomes, could have been the result of a site-specific recombination at the RNA level.


Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex.
Deficits in cognitive flexibility, the ability to modify behavior in response to changes in the environment, contribute to the onset and maintenance of stress-related neuropsychiatric illnesses, such as depression. Cognitive flexibility depends on medial prefrontal cortex (mPFC) function, and in depressed patients, cognitive inflexibility is associated with hypoactivity and decreased glutamate receptor expression in the mPFC. Rats exposed to chronic unpredictable stress (CUS) exhibit compromised mPFC function on the extradimensional (ED) set-shifting task of the attentional set-shifting test. Moreover, CUS-induced ED deficits are associated with dendritic atrophy and decreased glutamate receptor expression in the mPFC. This evidence suggests that impaired glutamate signaling may underlie stress-induced deficits in cognitive flexibility. To test this hypothesis, we first demonstrated that blocking NMDA or AMPA receptors in the mPFC during ED replicated CUS-induced deficits in naïve rats. Secondly, we found that expression of activity-regulated cytoskeleton-associated protein (Arc) mRNA, a marker of behaviorally induced glutamate-mediated plasticity, was increased in the mPFC following ED. We then showed that CUS compromised excitatory afferent activation of the mPFC following pharmacological stimulation of the mediodorsal thalamus (MDT), indicated by a reduced induction of c-fos expression. Subsequently, in vivo recordings of evoked potentials in the mPFC indicated that CUS impaired afferent activation of the mPFC evoked by MDT stimulation, but not the ventral hippocampus. Lastly, glutamate microdialysis showed that CUS attenuated the acute stress-evoked increase in extracellular glutamate in the mPFC. Together, these results demonstrate that CUS-induced ED deficits are associated with compromised glutamate neurotransmission in the mPFC.


Exploring trainer and trainee emotional talk in narratives about workplace-based feedback processes.
Emotion characterises learners' feedback experiences. While the failure-to-fail literature suggests that emotion may be important, little is known about the role of emotion for educators. Secondary analyses were therefore conducted on data exploring 110 trainers' and trainees' feedback experiences. Group and individual narrative interviews were conducted across three UK sites. We analysed 333 narratives for emotional talk using textual analysis: Linguistic Inquiry and Word Count. Furthermore, thematic framework analysis was conducted on the trainer narratives to explore aspects of feedback processes that are emotional. An additional in-depth little 'd' discourse analysis was conducted on selected trainer narratives to enable us to explore the complex relationship between the whats (reported events) and the hows (emotional talk). Trainer narratives did not differ significantly in positive or negative emotional talk from trainee narratives. By exploring the interplay of the whats and the hows, several aspects of feedback processes were identified as potentially emotional for trainers including trainers being concerned about upsetting learners and worried about patient safety. This was illustrated through numerous linguistic devices to establish emotional tone such as metaphoric talk and laughter. These findings suggest that feedback processes can be emotional for trainers. It highlights the need to better understand the 'filter' of emotion for trainers but also to better understand how emotion plays a role in feedback as a complex social process.


Influence of seasonality, air mass origin and particulate matter chemical composition on airborne bacterial community structure in the Po Valley, Italy.
The integration of chemical and biological data in aerosol studies represents a new challenge in atmospheric science. In this perspective it will be possible to gain a clearer and deeper comprehension of biogeochemical cycles in the atmosphere. In this view, this study aimed to investigate the relationships occurring between bacterial populations and PM chemical composition in one of the most polluted and urbanized areas in Europe: the Po Valley (Italy). Moreover, seasonality, long- and short-range transports were also evaluated to investigate the influence on airborne bacterial communities. PM samples were collected in two cities of the Po Valley (Milan and Venice) characterized by different meteorological conditions and atmospheric pollutant sources. Samples were analysed for water-soluble inorganic ions (WSIIs) and bacterial community structure. Chemical and biological data were jointly processed by using redundancy discriminate analysis (RDA), while the influence of atmospheric circulation was evaluated by using wind ground data and back-trajectories analysis. Results showed strong seasonal shifts of bacterial community structure in both cities, while a different behaviour was observed for air mass circulation at Milan ad Venice sites: long-range transport significantly affected bacterial populations in Milan whereas local ground wind had more influence in the Venice area. Moreover, difference in taxonomic composition can be mostly addressed to the characteristics of sampling sites. This evidence could suggest that, while PM composition is influenced by long-range transport, bacterial populations are affected, besides transport, by other factors (i.e., season and sampling site location). This perspective allow to better understand and explain airborne bacterial community behaviour.


[Effect of microelements on accumulation of biomass and exopolysaccharides in Bacillus subtilis strains].
Different trace elements in the composition of nine synthesized complex compounds of N-oxides of pyridine derivatives have been studied. It has been shown that the effect of trace elements included in the composition of nutrient media on accumulation of cells and exopolysaccharides (EPS) by the strains of B. subtilis is sufficiently expressed; it is also diverse and depends on the element nature, concentration as well as on peculiarities of the bacillus cultures. The studied trace elements are separated into the conditional groups: the elements intensifying the above processes (manganese and lithium); elements repressing the processes (copper and cadmium); those retarding the accumulation of biomass but activating the secretion of EPS (nickel, boron, cobalt, zinc, iron). Concentrations of trace elements optimal for the studied productivity indices of strains have been established. Peculiarities of the trace element effect in paired and ternary combinations on the growth and biosynthesis of EPS during cultivation of strains in liquid media have been revealed.


Bone mineral density reference values in Singaporean adults and comparisons for osteoporosis establishment - The Yishun Study.
While there have been studies in Singapore on the prevalence and economic burden of osteoporotic hip fracture, there is a severe lack of reference data on bone mineral density and prevalence of osteoporosis. The purpose of this study is to establish the reference values for BMD and compare prevalence of osteoporotic conditions using other available reference values so as to better understand the status of bone health in Singaporean adults. We carried out a population-based cross-sectional study using dual-energy x-ray absorptiometry (Hologic Discovery Wi) to measure the bone mineral density of Singaporean adults aged ≥21 years. A total of 542 participants were recruited from the large north-eastern residential town of Yishun. We computed T- scores (denoted by TSG) for each individual in the study. Similar diagnoses were also done based on T-scores provided by the densitometer (TDXA), NHANES database (TNHANES), and China (TCHN), and the differences in prevalence compared. We then compared the concordance between TSG and TDXA in the classification of osteoporosis. Osteoporosis was defined according to criteria by the World Health Organization (WHO). Peak lumbar spine BMD was 1.093 ± 0.168 g/cm2 in women, and 1.041 ± 0.098 g/cm2 for men. Peak whole-body BMD was 1.193 ± 0.93 g/cm2 in women at, and 1.224 ± 0.112 g/cm2 for men. Prevalence of osteoporosis based on lumbar spine was 9.3% in postmenopausal women, and 0.7% in men after 50 years of age. The percentage difference in prevalence range from 60.5-163.6%, when using reference values from TDXA, TNHANES, and TCHN. Comparing diagnosis using TDXA and TSG cut-off values, 28 versus 15 women were diagnosed as osteoporotic respectively.  The kappa statistics was 0.81 for women and 0.85 for men. Our study shows that T-scores provided by DXA manufacturer over-diagnosed osteoporosis in Singaporeans, and the prevalence of osteoporotic conditions is not accurately represented. This over-diagnosis may result in unnecessary treatment in some individuals.


Corneal biopsy in the management of progressive microbial keratitis.
To study the indications and role of diagnostic corneal biopsy in the management of patients with progressive microbial keratitis. The records of 33 consecutive patients who underwent a diagnostic corneal biopsy from January 1, 1986, to December 31, 1998, were reviewed. The indication for corneal biopsy was progressive infectious keratitis despite intensive broad-spectrum topical antimicrobial therapy, or progressive stromal infiltration inaccessible to corneal scrapings. Microbiologic evaluation of all corneal biopsies was performed, and 11 of the 33 biopsies were also examined histopathologically. A microorganism was isolated from 27 (82%) of the 33 corneal biopsies. Of the six patients with a negative biopsy, a penetrating keratoplasty was performed in five patients and the pathogen was identified by examination of the corneal button. In one patient no microorganism was identified; however, the infection resolved with topical antimicrobial therapy. The most common risk factor for keratitis was foreign body exposure or corneal abrasion (14 patients). A solid stromal infiltrate was the most common pattern of corneal involvement. Corneal biopsy revealed previously unidentified microorganisms that led to a change in antimicrobial therapy in 24 (89%) of the 27 patients and confirmed prior culture results in the remaining 3 patients. Microbiologic evaluation of the corneal biopsy was more sensitive than histopathologic examination. Acanthamoeba was the most commonly isolated pathogen (five cases), followed by Propionibacterium acnes and Fusarium (four cases each). Gram-positive organisms were isolated in 16 patients. Only five of the 27 patients with a positive corneal biopsy required a penetrating keratoplasty, in contrast to five of the six patients with a negative corneal biopsy (P =.005). During the 13-year period of the study, only three corneal biopsies were performed in the last 6 years. Microbiologic evaluation of a diagnostic corneal biopsy contributed significantly to the diagnosis, treatment, and outcome of patients with progressive infectious keratitis.


An empirical relationship between PM(2.5) and aerosol optical depth in Delhi Metropolitan.
Atmospheric remote sensing offers a unique opportunity to compute indirect estimates of air quality, which are critically important for the management and surveillance of air quality in megacities of developing countries, particularly in India and China, which have experienced elevated concentration of air pollution but lack adequate spatial-temporal coverage of air pollution monitoring. This article examines the relationship between aerosol optical depth (AOD) estimated from satellite data at 5 km spatial resolution and the mass of fine particles ≤2.5 μm in aerodynamic diameter (PM(2.5)) monitored on the ground in Delhi Metropolitan where a series of environmental laws have been instituted in recent years.PM(2.5) monitored at 113 sites were collocated by time and space with the AOD computed using the data from Moderate Resolution Imaging Spectroradiometer (MODIS onboard the Terra satellite). MODIS data were acquired from NASA's Goddard Space Flight Center Earth Sciences Distributed Active Archive Center (DAAC). Our analysis shows a significant positive association between AOD and PM(2.5). After controlling for weather conditions, a 1% change in AOD explains 0.52±0.202% and 0.39±0.15% change in PM(2.5) monitored within ±45 and 150 min intervals of AOD data. This relationship will be used to estimate air quality surface for previous years, which will allow us to examine the time-space dynamics of air pollution in Delhi following recent air quality regulations, and to assess exposure to air pollution before and after the regulations and its impact on health.


Progesterone Receptor Isoform Ratio: A Breast Cancer Prognostic and Predictive Factor for Antiprogestin Responsiveness.
Compelling evidence shows that progestins regulate breast cancer growth. Using preclinical models, we demonstrated that antiprogestins are inhibitory when the level of progesterone receptor isoform A (PR-A) is higher than that of isoform B (PR-B) and that they might stimulate growth when PR-B is predominant. The aims of this study were to investigate ex vivo responses to mifepristone (MFP) in breast carcinomas with different PR isoform ratios and to examine their clinical and molecular characteristics. We performed human breast cancer tissue culture assays (n = 36) to evaluate the effect of MFP on cell proliferation. PR isoform expression was determined by immunoblotting (n = 282). Tumors were categorized as PRA-H (PR-A/PR-B ≥ 1.2) or PRB-H (PR-A/PR-B ≤ 0.83). RNA was extracted for Ribo-Zero-Seq sequencing to evaluate differentially expressed genes. Subtypes and risk scores were predicted using the PAM50 gene set, the data analyzed using The Cancer Genome Atlas RNA-seq gene analysis and other publicly available gene expression data. Tissue microarrays were performed using paraffin-embedded tissues (PRA-H n = 53, PRB-H n = 24), and protein expression analyzed by immunohistochemistry. All statistical tests were two-sided. One hundred sixteen out of 222 (52.3%) PR+ tumors were PRA-H, and 64 (28.8%) PRB-H. Cell proliferation was inhibited by MFP in 19 of 19 tissue cultures from PRA-H tumors. A total of 139 transcripts related to proliferative pathways were differentially expressed in nine PRA-H and seven PRB-H tumors. PRB-H and PRA-H tumors were either luminal B or A phenotypes, respectively ( P = .03). PRB-H cases were associated with shorter relapse-free survival (hazard ratio [HR] = 2.70, 95% confidence interval [CI] = 1.71 to 6.20, P = .02) and distant metastasis-free survival (HR = 4.17, 95% CI = 2.18 to 7.97, P < .001). PRB-H tumors showed increased tumor size ( P < .001), Ki-67 levels ( P < .001), human epidermal growth factor receptor 2 expression ( P = .04), high grades ( P = .03), and decreased total PR ( P = .004) compared with PRA-H tumors. MUC-2 ( P < .001) and KRT6A ( P = .02) were also overexpressed in PRB-H tumors. The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer.


Expression and function of cytochrome p450-dependent enzymes in human skin cells.
Scientific interest in defining the human body's ability to limit the effects of administered drugs and xenobiotics dates from the mid-19th century when developing knowledge and techniques in the field of organic chemistry first made such studies possible. The first experimental evidence documenting the existence of cytochrome p450 (CYP) dates to the year 1955, when an enzyme system capable of oxidizing xenobiotic compounds was identified in the endoplasmic reticulum of liver homogenates. From these days on several studies analyzed the expression and function of metabolizing phase I enzymes in liver cells. Due to the unique structural features of human skin, little was known about the expression and function of CYP enzymes in this tissue and their role in uptake, metabolism and elimination of xenobiotics as well as endogenous substrates. Lasting recent years it has become clear that human skin cells express various CYP enzymes, including CYP26AI which is responsible for the metabolism of retinoic acid in skin cells. It has been also shown that CYP enzyme expression patterns are cell type and tissue specific and that in skin cells this differs significantly from its expression in other environmental interfaces such as the liver, lung and gastrointestinal tract. Therefore knowledge of skin-specific CYP expression and function is a prerequisite for pharmacological studies of the skin.


Inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells by the norsesterterpene peroxide, epimuqubilin A.
Seven norsesterterpene peroxides: epimuqubilin A (1), muqubilone B (2), unnamed cyclic peroxide ester (3), epimuqubilin B (4), sigmosceptrellin A methyl ester (5), sigmosceptrellin A (6), and sigmosceptrellin B methyl ester (7), isolated from the marine sponge Latrunculia sp., were examined with regard to their effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells. The results indicated epimuqubilin A (1) possessed potent NO inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide release with an IC(50) value of 7.4 microM, a level three times greater than the positive control, L-N(G)-monomethyl arginine citrate, followed by 6 (sigmosceptrellin A, IC(50) = 9.9 microM), whereas other compounds exhibited only modest activity (Table 1). These compounds did not show appreciable cytotoxicity at their IC(50) values for NO-inhibitory activity. The structure-activity upon NO inhibition could be summarized as follows: (1) a monocyclic carbon skeleton framework was essential for activity, (2) free acids gave higher activity, (3) the orientation of H3-22 with an equatorial position increased activity, and (4) a bicyclic structure reduced activity. This is the first report of a norsesterterpene peroxide with NO-inhibitory activity. In addition, compounds 1-7 were also evaluated for their inhibitory activities in the yeast glycogen synthase kinase-3beta assay. In summary, several norsesterterpene peroxides showed novel biological activities of inhibition in NO production, suggesting that these might provide leads for anti-inflammatory or cancer chemopreventive agents.


The matrix-binding domain of microfibril-associated glycoprotein-1 targets active connective tissue growth factor to a fibroblast-produced extracellular matrix.
It is advantageous to use biomaterials in tissue engineering that stimulate extracellular matrix (ECM) production by the cellular component. Connective tissue growth factor (CTGF) stimulates type I collagen (COL1A1) transcription, but is functionally limited as a free molecule. Using a matrix-binding domain (MBD) from microfibril-associated glycoprotein-1, the fusion protein MBD-CTGF was targeted to the ECM and tested for COL1A1 transcriptional activation. MBD-CTGF produced by the ECM-synthesizing fibroblasts, or provided exogenously, localized to the elastic fiber ECM. MBD-CTGF, but not CTGF alone, led to a two-fold enhancement of COL1A1 expression. This study introduces a targeting technology that can be used to elevate collagen transcription in engineered tissues and thereby improve tissue mechanics.


Barriers to palliative care for children: perceptions of pediatric health care providers.
The goal was to explore barriers to palliative care experienced by pediatric health care providers caring for seriously ill children. This study explored pediatric provider perceptions of end-of-life care in an academic children's hospital, with the goal of describing perceived barriers to end-of-life care for children and their families. The report focuses on the responses of nurses (n = 117) and physicians (n = 81). Approximately one half of the respondents reported 4 of 26 barriers listed in the study questionnaire as frequently or almost always occurring, that is, uncertain prognosis (55%), family not ready to acknowledge incurable condition (51%), language barriers (47%), and time constraints (47%). Approximately one third of respondents cited another 8 barriers frequently arising from problems with communication and from insufficient education in pain and palliative care. Fourteen barriers were perceived by >75% of staff members as occasionally or never interfering with pediatric end-of-life care. Comparisons between physicians and nurses and between ICU and non-ICU staff members revealed several significant differences between these groups. Perceived barriers to pediatric end-of-life care differed from those impeding adult end-of-life care. The most-commonly perceived factors that interfered with optimal pediatric end-of-life care involved uncertainties in prognosis and discrepancies in treatment goals between staff members and family members, followed by barriers to communication. Improved staff education in communication skills and palliative care for children may help overcome some of these obstacles, but pediatric providers must realize that uncertainty may be unavoidable and inherent in the care of seriously ill children. An uncertain prognosis should be a signal to initiate, rather than to delay, palliative care.