title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Molecular cloning, phylogenetic analysis and expression of a MAPEG superfamily gene from the pufferfish Takifugu obscurus. | The microsomal glutathione S-transferases (MGSTs) of membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) superfamily play an important role in xenobiotics detoxification. Compared to mammals, there is limited information on MAPEGS from fish. We cloned a full length of cDNA sequence of a MGST gene from the river pufferfish (Takifugu obscurus), studied its phylogenetic relationship, and measured its expression in different tissues and in liver of fish exposed to cadmium. Phylogenetic analysis revealed that the identified gene encoded for MGST3. Liver showed the highest expression of MGST3 transcripts. When MSGT expression was compared with the expression of other GSTs (GST-Alpha, GST-Mu and GST-Theta), a similar pattern of highest expression was observed in the liver. Upon Cd exposure (5 ppm) for 96 h, the highest expression of MGST was observed at 24 h. GST-Mu also showed highest expression at 24 h. These findings indicate that MGSTs may be playing a role in detoxification of xenobiotics or free radicals generated by Cd-induced oxidative stress in fish. | 18,832,047 |
Morphometrics applied to medical entomology. | Morphometrics underwent a revolution more than one decade ago. In the modern morphometrics, the estimate of size is now contained in a single variable reflecting variation in many directions, as many as there are landmarks under study, and shape is defined as their relative positions after correcting for size, position and orientation. With these informative data, and the corresponding software freely available to conduct complex analyses, significant biological and epidemiological features can be quantified more accurately. We discuss the evolutionary significance of the environmental impact on metric variability, mentioning the importance of concepts like genetic assimilation, genetic accommodation, and epigenetics. We provide examples of measuring the effect of selection on metric variation by comparing (unpublished) Qst values with corresponding (published) Fst. The primary needs of medical entomologists are to distinguish species, especially cryptic species, and to detect them where they are not expected. We explain how geometric morphometrics could apply to these questions, and where there are deficiencies preventing the approach from being utilized at its maximum potential. Medical entomologists in connection with control programs aim to identify isolated populations where the risk of reinfestation after treatment would be low ("biogeographical islands"). Identifying them can be obtained from estimating the number of migrants per generation. Direct assessment of movement remains the most valid approach, but it scores active movement only. Genetic methods estimating gene flow levels among interbreeding populations are commonly used, but gene flow does not necessarily mean the current flow of migrants. Methods using the morphometric variation are neither suited to evaluate gene flow, nor are they adapted to estimate the flow of migrants. They may provide, however, the information needed to create a preliminary map pointing to relevant areas where one could invest in using molecular machinery. In case of reinfesting specimens after treatment, the question relates to the likely source of reinfesting specimens: are they a residual sample not affected by the control measures, or are they individuals migrating from surrounding, untreated foci? We explain why the morphometric approach may be adapted to answer such question. Thus, we describe the differences between estimating the flow of migrants and identifying the source of reinfestation after treatment: although morphometrics is not suited to deal with the former, it may be an appropriate tool to address the latter. | 18,832,048 |
Life history of a basal bird: morphometrics of the Early Cretaceous Confuciusornis. | Confuciusornis sanctus stands out among the remarkable diversity of Mesozoic birds recently unearthed from China. Not only is this primitive beaked pygostylian (birds with abbreviated caudal vertebrae fused into a pygostyle) much more abundant than other avian taxa of this age but differences in plumage between specimens--some having a pair of long stiff tail feathers--have been interpreted as evidence for the earliest example of sexual dimorphism in birds. We report the results of a multivariate morphometric study involving measurements of more than 100 skeletons of C. sanctus. Our analyses do not show any correlation between size distribution and the presence or absence of blade-like rectrices (tail feathers), thus implying, that if these feathers are sexual characters, they are not correlated with sexual size dimorphism. Our results also provide insights into the taxonomy and life history of confuciusornithids, suggesting that these birds may have retained ancestral dinosaurian growth patterns characterized by a midlife exponential growth stage. | 18,832,054 |
Experimental evolution of a microbial predator's ability to find prey. | Foraging theory seeks to explain how the distribution and abundance of prey influence the evolution of predatory behaviour, including the allocation of effort to searching for prey and handling them after they are found. While experiments have shown that many predators alter their behaviour phenotypically within individual lifetimes, few have examined the actual evolution of predatory behaviour in light of this theory. Here, we test the effects of prey density on the evolution of a predator's searching and handling behaviours using a bacterial predator, Myxococcus xanthus. Sixteen predator populations evolved for almost a year on agar surfaces containing patches of Escherichia coli prey at low or high density. Improvements in searching rate were significantly greater in those predators that evolved at low prey density. Handling performance also improved in some predator populations, but prey density did not significantly affect the magnitude of these gains. As the predators evolved greater foraging proficiency, their capacity diminished to produce fruiting bodies that enable them to survive prolonged periods of starvation. More generally, these results demonstrate that predators evolve behaviours that reflect at least some of the opportunities and limitations imposed by the distribution and abundance of their prey. | 18,832,061 |
Polo-like kinase Cdc5 drives exit from pachytene during budding yeast meiosis. | In budding yeast, exit from the pachytene stage of meiosis requires the mid-meiosis transcription factor Ndt80, which promotes expression of approximately 200 genes. Ndt80 is required for meiotic function of polo-like kinase (PLK, Cdc5) and cyclin-dependent kinase (CDK), two cell cycle kinases previously implicated in pachytene exit. We show that ongoing CDK activity is dispensable for two events that accompany exit from pachytene: crossover formation and synaptonemal complex breakdown. In contrast, CDC5 expression in ndt80Delta mutants efficiently promotes both events. Thus, Cdc5 is the only member of the Ndt80 transcriptome required for this critical step in meiotic progression. | 18,832,066 |
Histone deacetylase 3 is required for centromeric H3K4 deacetylation and sister chromatid cohesion. | We describe here the role of histone deacetylase 3 (HDAC3) in sister chromatid cohesion and the deacetylation of histone H3 Lys 4 (H3K4) at the centromere. HDAC3 knockdown induced spindle assembly checkpoint activation and sister chromatid dissociation. The depletion of Polo-like kinase 1 (Plk1) or Aurora B restored cohesion in HDAC3-depleted cells. HDAC3 was also required for Shugoshin localization at centromeres. Finally, we show that HDAC3 depletion results in the acetylation of centromeric H3K4, correlated with a loss of dimethylation at the same position. These findings provide a functional link between sister chromatid cohesion and the mitotic "histone code". | 18,832,068 |
Role of Cdx2 and cell polarity in cell allocation and specification of trophectoderm and inner cell mass in the mouse embryo. | Genesis of the trophectoderm and inner cell mass (ICM) lineages occurs in two stages. It is initiated via asymmetric divisions of eight- and 16-cell blastomeres that allocate cells to inner and outer positions, each with different developmental fates. Outside cells become committed to the trophectoderm at the blastocyst stage through Cdx2 activity, but here we show that Cdx2 can also act earlier to influence cell allocation. Increasing Cdx2 levels in individual blastomeres promotes symmetric divisions, thereby allocating more cells to the trophectoderm, whereas reducing Cdx2 promotes asymmetric divisions and consequently contribution to the ICM. Furthermore, both Cdx2 mRNA and protein levels are heterogeneous at the eight-cell stage. This heterogeneity depends on cell origin and has developmental consequences. Cdx2 expression is minimal in cells with unrestricted developmental potential that contribute preferentially to the ICM and is maximal in cells with reduced potential that contribute more to the trophectoderm. Finally, we describe a mutually reinforcing relationship between cellular polarity and Cdx2: Cdx2 influences cell polarity by up-regulating aPKC, but cell polarity also influences Cdx2 through asymmetric distribution of Cdx2 mRNA in polarized blastomeres. Thus, divisions generating inside and outside cells are truly asymmetric with respect to cell fate instructions. These two interacting effects ensure the generation of a stable outer epithelium by the blastocyst stage. | 18,832,072 |
Modular control analysis of effects of chronic hypoxia on mouse heart. | Modular control analysis (MoCA; Diolez P, Deschodt-Arsac V, Raffard G, Simon C, Santos PD, Thiaudiere E, Arsac L, Franconi JM. Am J Physiol Regul Integr Comp Physiol 293: R13-R19, 2007) was applied here on perfused hearts to describe the modifications of the regulation of heart energetics induced in mice exposed to 3-wk chronic hypoxia. MoCA combines 31P-NMR spectroscopy and modular (top down) control analysis to describe the integrative regulation of energy metabolism in the intact beating heart, on the basis of two modules [ATP/phosphocreatine (PCr) production and ATP/PCr consumption] connected by the energetic intermediates. In contrast with previous results in rat heart, in which all control of contraction was on ATP demand, mouse heart energetics presented a shared control of contraction between ATP/PCr-producing and -consuming modules. In chronic hypoxic mice, the decrease in heart contractile activity and PCr-to-ATP ratio was surprisingly associated with an important and significant higher response of ATP/PCr production (elasticity) to PCr changes compared with control hearts (-10.4 vs. -2.46). By contrast, no changes were observed in ATP/PCr consumption since comparable elasticities were observed. Since elasticities determine the regulation of energetics of heart contraction, the present results show that this new parameter may be used to uncover the origin of the observed dysfunctions under chronic hypoxia conditions. Considering the decrease in mitochondrial content reported after exposure to chronic hypoxia, it appears that the improvement of ATP/PCr production response to ATP demand may be viewed as a positive adaptative mechanism. It now appears crucial to understand the very processes responsible for ATP/PCr producer elasticity toward the energetic intermediates, as well as their regulation. | 18,832,083 |
Comparative study of selective chromogenic (chromID VRE) and bile esculin agars for isolation and identification of vanB-containing vancomycin-resistant enterococci from feces and rectal swabs. | The new chromogenic agar chromID VRE (cIDVRE; bioMérieux) was compared with bile esculin agar (BD) containing 6 mg/liter vancomycin for the detection of colonization with vanB-containing vancomycin-resistant enterococci (VRE). At 48 h of incubation, the results obtained with both media were comparable. However, cIDVRE detected significantly more VRE at 24 h (39.3% versus 21.3%, P = 0.003), and its use may facilitate the timely implementation of infection control procedures. | 18,832,121 |
Genetic relatedness of Clostridium difficile isolates from various origins determined by triple-locus sequence analysis based on toxin regulatory genes tcdC, tcdR, and cdtR. | A triple-locus nucleotide sequence analysis based on toxin regulatory genes tcdC, tcdR and cdtR was initiated to assess the sequence variability of these genes among Clostridium difficile isolates and to study the genetic relatedness between isolates. A preliminary investigation of the variability of the tcdC gene was done with 57 clinical and veterinary isolates. Twenty-three isolates representing nine main clusters were selected for tcdC, tcdR, and cdtR analysis. The numbers of alleles found for tcdC, tcdR and cdtR were nine, six, and five, respectively. All strains possessed the cdtR gene except toxin A-negative toxin B-positive variants. All but one binary toxin CDT-positive isolate harbored a deletion (>1 bp) in the tcdC gene. The combined analyses of the three genes allowed us to distinguish five lineages correlated with the different types of deletion in tcdC, i.e., 18 bp (associated or not with a deletion at position 117), 36 bp, 39 bp, and 54 bp, and with the wild-type tcdC (no deletion). The tcdR and tcdC genes, though located within the same pathogenicity locus, were found to have evolved separately. Coevolution of the three genes was noted only with strains harboring a 39-bp or a 54-bp deletion in tcdC that formed two homogeneous, separate divergent clusters. Our study supported the existence of the known clones (PCR ribotype 027 isolates and toxin A-negative toxin B-positive C. difficile variants) and evidence for clonality of isolates with a 39-bp deletion (toxinotype V, PCR ribotype 078) that are frequently isolated worldwide from human infections and from food animals. | 18,832,125 |
A minimalist network model for coarse-grained normal mode analysis and its application to biomolecular x-ray crystallography. | In this article, we report a method for coarse-grained normal mode analysis called the minimalist network model. The main features of the method are that it can deliver accurate low-frequency modes on structures without undergoing initial energy minimization and that it also retains the details of molecular interactions. The method does not require any additional adjustable parameters after coarse graining and is computationally very fast. Tests on modeling the experimentally measured anisotropic displacement parameters in biomolecular x-ray crystallography demonstrate that the method can consistently perform better than other commonly used methods including our own one. We expect this method to be effective for applications such as structural refinement and conformational sampling. | 18,832,168 |
Loss of Rb1 in the gastrointestinal tract of Apc1638N mice promotes tumors of the cecum and proximal colon. | To examine the role of Rb1 in gastrointestinal (GI) tumors, we generated mice with an Apc(1638N) allele, Rb(tm2brn) floxed alleles, and a villin-cre transgene (RBVCA). These animals had exon 19 deleted from Rb1 throughout the GI tract. We have shown previously that Rb1 deficiency is insufficient for GI tumor initiation, with inactivation of an Apc allele capable of overcoming the insufficiency. In this study we demonstrate that RBVCA mice have reduced median survival because of an increase in tumor incidence and multiplicity in the cecum and the proximal colon. Large intestinal tumors are predominantly adenomas, whereas the tumors of the small intestine are a mixture of adenomas and adenocarcinomas. We find truncation mutations to the second Apc allele in tumors of both the large and small intestine. Expression profiles of duodenal and cecal tumors relative to each other show unique gene subsets up and down regulated. Substantial expression patterns compare to human colorectal cancer, including recapitulation of embryonic genes. Our results indicate that Rb1 has significant influence over tumor location in the GI tract, and that both cecal and duodenal tumors initiate through inactivation of Apc. Expression profile analysis indicates the two tumor types differentially regulate distinct sets of genes that are over-expressed in a majority of human colorectal carcinomas. | 18,832,169 |
Hippocampal-dependent learning requires a functional circadian system. | Decades of studies have shown that eliminating circadian rhythms of mammals does not compromise their health or longevity in the laboratory in any obvious way. These observations have raised questions about the functional significance of the mammalian circadian system, but have been difficult to address for lack of an appropriate animal model. Surgical ablation of the suprachiasmatic nucleus (SCN) and clock gene knockouts eliminate rhythms, but also damage adjacent brain regions or cause developmental effects that may impair cognitive or other physiological functions. We developed a method that avoids these problems and eliminates rhythms by noninvasive means in Siberian hamsters (Phodopus sungorus). The present study evaluated cognitive function in arrhythmic animals by using a hippocampal-dependent learning task. Control hamsters exhibited normal circadian modulation of performance in a delayed novel-object recognition task. By contrast, arrhythmic animals could not discriminate a novel object from a familiar one only 20 or 60 min after training. Memory performance was not related to prior sleep history as sleep manipulations had no effect on performance. The GABA antagonist pentylenetetrazol restored learning without restoring circadian rhythms. We conclude that the circadian system is involved in memory function in a manner that is independent of sleep. Circadian influence on learning may be exerted via cyclic GABA output from the SCN to target sites involved in learning. Arrhythmic hamsters may have failed to perform this task because of chronic inhibitory signaling from the SCN that interfered with the plastic mechanisms that encode learning in the hippocampus. | 18,832,172 |
Biomechanical ordering of dense cell populations. | The structure of bacterial populations is governed by the interplay of many physical and biological factors, ranging from properties of surrounding aqueous media and substrates to cell-cell communication and gene expression in individual cells. The biomechanical interactions arising from the growth and division of individual cells in confined environments are ubiquitous, yet little work has focused on this fundamental aspect of colony formation. We analyze the spatial organization of Escherichia coli growing in a microfluidic chemostat. We find that growth and expansion of a dense colony of cells leads to a dynamical transition from an isotropic disordered phase to a nematic phase characterized by orientational alignment of rod-like cells. We develop a continuum model of collective cell dynamics based on equations for local cell density, velocity, and the tensor order parameter. We use this model and discrete element simulations to elucidate the mechanism of cell ordering and quantify the relationship between the dynamics of cell proliferation and the spatial structure of the population. | 18,832,176 |
Filling the concept with data: integrating data from different in vitro and in silico assays on skin sensitizers to explore the battery approach for animal-free skin sensitization testing. | Tests for skin sensitization are required prior to the market launch of new cosmetic ingredients. Significant efforts are made to replace the current animal tests. It is widely recognized that this cannot be accomplished with a single in vitro test, but that rather the integration of results from different in vitro and in silico assays will be needed for the prediction of the skin sensitization potential of chemicals. This has been proposed as a theoretical scheme so far, but no attempts have been made to use experimental data to prove the validity of this concept. Here we thus try for the first time to fill this widely cited concept with data. To this aim, we integrate and report both novel and literature data on 116 chemicals of known skin sensitization potential on the following parameters: (1) peptide reactivity as a surrogate for protein binding, (2) induction of antioxidant/electrophile responsive element dependent luciferase activity as a cell-based assay; (3) Tissue Metabolism Simulator skin sensitization model in silico prediction; and (4) calculated octanol-water partition coefficient. The results of the in vitro assays were scaled into five classes from 0 to 4 to give an in vitro score and compared to the local lymph node assay (LLNA) data, which were also scaled from 0 to 4 (nonsensitizer/weak/moderate/strong/extreme). Different ways of evaluating these data have been assessed to rate the hazard of chemicals (Cooper statistics) and to also scale their potency. With the optimized model an overall accuracy for predicting sensitizers of 87.9% was obtained. There is a linear correlation between the LLNA score and the in vitro score. However, the correlation needs further improvement as there is still a relatively high variation in the in vitro score between chemicals belonging to the same sensitization potency class. | 18,832,184 |
Effect of minor milk proteins in chymosin separated whey and casein fractions on cheese yield as determined by proteomics and multivariate data analysis. | The objective of this work was to find regressions between minor milk proteins or protein fragments in the casein or sweet whey fraction and cheese yield because the effect of major milk proteins was evaluated in a previous study. Proteomic methods involving 2-dimensional gel electrophoresis and mass spectrometry in combination with multivariate data analysis were used to study the effect of variations in milk protein composition in chymosin separated whey and casein fractions on cheese yield. By mass spectrometry, a range of proteins significant for the cheese yield was identified. Among others, a C-terminal fragment of beta-casein had a positive effect on the cheese yield expressed as grams of cheese per 100 g of milk, whereas several other minor fragments of beta-, alpha(s1)-, and alpha(s2)-casein had positive effects on the transfer of protein from milk to cheese. However, the individual effect of each identified protein was relatively low. Therefore, further studies of the relations between different proteins/peptides in the rennet casein or sweet whey fractions and cheese yield are needed for advanced understanding and prediction of cheese yield. | 18,832,200 |
Cleanliness scores as indicator of Klebsiella exposure in dairy cows. | This study was designed to explore the relationship between cow and udder cleanliness scores and the risk of isolation of Klebsiella spp. from lower hind legs and teat ends, respectively. The distribution of Klebsiella species was compared among isolates from teat ends, legs, and cases of clinical mastitis obtained from 2 dairy farms in New York State, with 850 and 1,000 cows, respectively. Farms were visited twice approximately 4 wk apart in August and September 2007 to obtain cleanliness scores and swabs from legs and teats. Isolates of Klebsiella clinical mastitis from each farm were collected from July through October 2007. Two studies were conducted. In the first study, whole-cow cleanliness of a purposive sample of 200 lactating cows was scored using a 4-point scale, and swabs were taken from their lower hind legs. In the second study, udder cleanliness of a separate convenience sample of 199 lactating cows was scored in the milking parlor, and swabs were taken from their teat ends before and after premilking udder preparation. Prevalence of Klebsiella spp. on legs and teat ends before udder preparation was 59 and 60%, respectively. Logistic regression was used to explore the association between isolation of Klebsiella spp. and cleanliness scores. Cow cleanliness scores and udder cleanliness scores were not associated with detection of Klebsiella on legs and on teats before udder preparation, respectively. After udder preparation, 43% of previously Klebsiella positive teat end samples remained positive, with significant differences between farms and months. Teats from dirty udders were significantly more likely to test positive for Klebsiella after udder preparation than teats from clean udders. The proportion of Klebsiella pneumoniae and Klebsiella oxytoca isolates was similar for isolates from teat end swabs and clinical mastitis cases, supporting the notion that the presence of Klebsiella on teat ends may lead to opportunistic intramammary infections. Udder cleanliness scores could be used as a management tool to monitor the risk of exposure to Klebsiella spp. on teat ends. | 18,832,213 |
Short communication: malic acid does not promote vaccenic acid accumulation in mixed ruminal fluid with fractionated fish oil by a rumen-simulation technique. | The objective of this study was to determine whether malic acid could promote the accumulation of vaccenic acid in the rumen. The control diet was composed of a 65:35 ratio of forage to concentrate with 1% (dry matter basis) added fractionated fish oil (rich in docosahexaenoic acid), and treatment diets consisted of the control diet with added malic acid to achieve final concentrations of 10 mM (treatment 1) and 20 mM (treatment 2), respectively. The experiment was conducted with rumen-simulation equipment (Rusitec) consisting of 9 fermenters. Each treatment included 3 fermenters as replicates. After 7 d of incubation, concentrations of vaccenic acid from treatment 1 (4.38% fatty acids) and treatment 2 (4.46% fatty acids) were similar to that of the control treatment (4.51% fatty acids). The disappearance of docosahexaenoic acid was not different among the control, treatment 1, or treatment 2. These data indicated that malic acid did not promote the accumulation of vaccenic acid in ruminal fluid. | 18,832,223 |
Genetic relationship between culling, milk production, fertility, and health traits in Norwegian red cows. | First-lactation records on 836,452 daughters of 3,064 Norwegian Red sires were used to examine associations between culling in first lactation and 305-d protein yield, susceptibility to clinical mastitis, lactation mean somatic cell score (SCS), nonreturn rate within 56 d in heifers and primiparous cows, and interval from calving to first insemination. A Bayesian multivariate threshold-linear model was used for analysis. Posterior mean of heritability of liability to culling of primiparous cows was 0.04. The posterior means of the genetic correlations between culling and the other traits were -0.41 to 305-d protein yield, 0.20 to lactation mean SCS, 0.36 to clinical mastitis, 0.15 to interval from calving to first insemination, -0.11 to 56-d nonreturn as heifer, and -0.04 to 56-d nonreturn as primiparous cow. As much as 66% of the genetic variation in culling was explained by genetic variation in protein yield, clinical mastitis, interval of calving to first insemination, and 56-d nonreturn in heifers, whereas contribution from the SCS and 56-d nonreturn as primiparous cow was negligible, after taking the other traits into account. This implies that for breeds selected for a broad breeding goal, including functional traits such as health and fertility, most of the genetic variation in culling will probably be covered by other traits in the breeding goal. However, in populations where data on health and fertility is scarce or not available at all, selection against early culling may be useful in indirect selection for improved health and fertility. Regression of average sire posterior mean on birth-year of the sire indicate a genetic change equivalent to an annual decrease of the probability of culling in first-lactation Norwegian Red cattle by 0.2 percentage units. This genetic improvement is most likely a result of simultaneous selection for improved milk yield, health, and fertility over the last decades. | 18,832,226 |
Genetic correlation patterns between somatic cell score and protein yield in the Italian Holstein-Friesian population. | Genetic parameters for somatic cell score (SCS) in the Italian Holstein-Friesian population were estimated addressing the pattern of genetic correlation with protein yield in different parities (first, second, and third) and on different days in milk within each parity. Three approaches for parameter estimation were applied using random samples of herds from the national database of the Italian Holstein Association. Genetic correlations for lactation measures (305-d protein yield and lactation SCS) were positive in the first parity (0.31) and close to zero in the second (0.01) and third (0.09) parities. These results indicated that larger values of SCS were genetically associated with increased production. The second and third sets of estimates were based on random regression test-day models, modeling the shape of lactation curve with the Wilmink function and fourth-order Legendre polynomials, respectively. Genetic correlations from both random regression models showed a specific pattern associated with days in milk within and across parities. Estimates varied from positive to negative in the first and second parity, and from null to negative in the third parity. Patterns were similar for both random regression models. The average overall correlation between SCS and protein yield was zero or slightly positive in the first lactation and ranged from zero to negative in later lactations. Correlation estimates differed by parity and stage of lactation. They also demonstrated the dubiousness of applying a single genetic correlation measure between SCS and protein in setting selection strategies. Differences in magnitude and the sign of genetic correlations between SCS and yields across and within parities should be accounted for in selection schemes. | 18,832,227 |
Psychosocial factors related to diet among women with recent gestational diabetes: opportunities for intervention. | This study investigated postpartum dietary behaviors among women with recent gestational diabetes mellitus (GDM), the cognitive and social factors related to these, and preferred types of lifestyle support, in order improve the development of diabetes prevention strategies for this group. Participants were a random sample of 226 women diagnosed with GDM in the prior 6 to 24 months. Telephone surveys were used to evaluate dietary behaviors, self-efficacy, social support, perceived barriers to healthy eating, and preferred methods of lifestyle support. Only 5% of the respondents consumed 5 servings/day of vegetables and 44% consumed 2 or more servings/day of fruit. Fried food was eaten at least twice per week by 26% of women and 50% usually consumed full-fat milk. Higher vegetable consumption was associated with self-efficacy to cook healthy foods, reporting that a healthy diet is not a difficult change and that dislike of healthy foods by other household members is not a barrier. Fruit consumption was positively related to self-efficacy when busy and when not reporting a dislike of healthy foods by others at home. Advice from a dietitian and telephone support from a health educator were the most preferred forms of health assistance. Dietary risks factors are prevalent among women with recent GDM. Confidence and skills in cooking healthy foods, along with family food preferences and time pressures, are important influences on eating habits. Dietary change programs, informed by the beliefs and circumstances of this high-risk population, need to be developed. | 18,832,285 |
Effect of carbon source availability and growth phase on expression of Corynebacterium glutamicum genes involved in the tricarboxylic acid cycle and glyoxylate bypass. | The effect of different carbon sources on the expression of tricarboxylic acid (TCA) cycle genes, along with glyoxylate bypass genes, in Corynebacterium glutamicum was determined. All TCA cycle genes were coordinately expressed in medium containing acetate. Growth in the presence of acetate gave rise to abundant expression of most TCA cycle genes, with the level of gltA transcript being the highest. However, when the cells entered the stationary phase triggered by acetate exhaustion, all genes were repressed, except sucCD and mdhB, which were slightly induced. Acetate withdrawal from the growth medium during the exponential phase also led to rapid repression of most TCA cycle genes and a corresponding twofold increase in the expression of sucCD, which were strongly induced by citrate and succinate. In addition, glucose depletion during the stationary phase led to a corresponding 8-20-fold induction of the sucCD, aceA and aceB genes. Addition of glucose to acetate medium resulted in about 10-fold induction of sucCD. The strong dependence of TCA cycle sucCD and glyoxylate bypass aceA and aceB expression on carbon source availability was confirmed and the regulatory system will be studied precisely. | 18,832,313 |
Aromatic degradative pathways in Acinetobacter baylyi underlie carbon catabolite repression. | Carbon catabolite repression is an important mechanism allowing efficient carbon source utilization. In the soil bacterium Acinetobacter baylyi, this mechanism has been shown to apply to the aromatic degradative pathways for the substrates protocatechuate, p-hydroxybenzoate and vanillate. In this investigation, transcriptional fusions with the gene for luciferase in the gene clusters for the degradation of benzyl esters, anthranilate, benzoate, hydroxycinnamates and dicarboxylates (are, ant, ben, hca and dca genes) were constructed and established in the chromosome of A. baylyi. The respective strains revealed the presence of strong carbon catabolite repression at the transcriptional level. In all cases, succinate and acetate in combination had the strongest repressing effect, and pyruvate (or lactate in case of the ben and hca genes) allowed the highest expression when these carbon sources were supplied together with the respective inducer. The pattern of repression for the different cosubstrates was similar for all operons investigated and was also observed in the absence of the respective inducing compounds, indicating a mechanism that is independent of the respective specific regulators. Repression by acetate and succinate varied between 88 % for the hca genes and 99 % for the pca genes. | 18,832,315 |
Detection of small RNAs in Pseudomonas aeruginosa by RNomics and structure-based bioinformatic tools. | Inactivation of the Pseudomonas aeruginosa (PAO1) hfq gene, encoding the Sm-like Hfq protein, resulted in pleiotropic effects that included an attenuated virulence. As regulation by Hfq often involves the action of small regulatory RNAs (sRNAs), we have used a shotgun cloning approach (RNomics) and bioinformatic tools to identify sRNAs in strain PAO1. For cDNA library construction, total RNA was extracted from PAO1 cultures either grown to stationary phase or exposed to human serum. The cDNA libraries were generated from small-sized RNAs of PAO1 after co-immunoprecipitation with Hfq. Of 400 sequenced cDNA clones, 11 mapped to intergenic regions. Band-shift assays and Northern blot analyses performed with two selected sRNAs confirmed that Hfq binds to and affects the steady-state levels of these RNAs. A proteome study performed upon overproduction of one sRNA, PhrS, implicated it in riboregulation. PhrS contains an ORF, and evidence for its translation is presented. In addition, based on surveys with structure-based bioinformatic tools, we provide an electronic compilation of putative sRNA and non-coding RNA genes of PAO1 based on their evolutionarily conserved structure. | 18,832,323 |
The spindle positioning protein Kar9p interacts with the sumoylation machinery in Saccharomyces cerevisiae. | Accurate positioning of the mitotic spindle is important for the genetic material to be distributed evenly in dividing cells, but little is known about the mechanisms that regulate this process. Here we report that two microtubule-associated proteins important for spindle positioning interact with several proteins in the sumoylation pathway. By two-hybrid analysis, Kar9p and Bim1p interact with the yeast SUMO Smt3p, the E2 enzyme Ubc9p, an E3 Nfi1p, as well as Wss1p, a weak suppressor of a temperature-sensitive smt3 allele. The physical interaction between Kar9p and Ubc9p was confirmed by in vitro binding assays. A single-amino-acid substitution in Kar9p, L304P disrupted its two-hybrid interaction with proteins in the sumoylation pathway, but retained its interactions with the spindle positioning proteins Bim1p, Stu2p, Bik1p, and Myo2p. The kar9-L304P mutant showed defects in positioning the mitotic spindle, with the spindle located more distally than normal. Whereas wild-type Kar9p-3GFP normally localizes to only the bud-directed spindle pole body (SPB), Kar9p-L304P-3GFP was mislocalized to both SPBs. Using a reconstitution assay, Kar9p was sumoylated in vitro. We propose a model in which sumoylation regulates spindle positioning by restricting Kar9p to one SPB. These findings raise the possibility that sumoylation could regulate other microtubule-dependent processes. | 18,832,349 |
CleanEST: a database of cleansed EST libraries. | The EST division of GenBank, dbEST, is widely used in many applications such as gene discovery and verification of exon-intron structure. However, the use of EST sequences in the dbEST libraries is often hampered by inconsistent terminology used to describe the library sources and by the presence of contaminated sequences. Here, we describe CleanEST, a novel database server that classified dbEST libraries and removes contaminants. We classified all dbEST libraries according to species and sequencing center. In addition, we further classified human EST libraries by anatomical and pathological systems according to eVOC ontologies. For each dbEST library, we provide two different cleansed sequences: 'pre-cleansed' and 'user-cleansed'. To generate pre-cleansed sequences, we cleansed sequences in dbEST by alignment of EST sequences against well-known contamination sources: UniVec, Escherichia coli, mitochondria and chloroplast (for plant). To provide user-cleansed sequences, we built an automatic user-cleansing pipeline, in which sequences of a user-selected library are cleansed on-the-fly according to user-selected options. The server is available at http://cleanest.kobic.re.kr/ and the database is updated monthly. | 18,832,365 |
Modeling genetic inheritance of copy number variations. | Copy number variations (CNVs) are being used as genetic markers or functional candidates in gene-mapping studies. However, unlike single nucleotide polymorphism or microsatellite genotyping techniques, most CNV detection methods are limited to detecting total copy numbers, rather than copy number in each of the two homologous chromosomes. To address this issue, we developed a statistical framework for intensity-based CNV detection platforms using family data. Our algorithm identifies CNVs for a family simultaneously, thus avoiding the generation of calls with Mendelian inconsistency while maintaining the ability to detect de novo CNVs. Applications to simulated data and real data indicate that our method significantly improves both call rates and accuracy of boundary inference, compared to existing approaches. We further illustrate the use of Mendelian inheritance to infer SNP allele compositions in each of the two homologous chromosomes in CNV regions using real data. Finally, we applied our method to a set of families genotyped using both the Illumina HumanHap550 and Affymetrix genome-wide 5.0 arrays to demonstrate its performance on both inherited and de novo CNVs. In conclusion, our method produces accurate CNV calls, gives probabilistic estimates of CNV transmission and builds a solid foundation for the development of linkage and association tests utilizing CNVs. | 18,832,372 |
An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart. | In order to understand how secreted signals regulate complex morphogenetic events, it is crucial to identify their cellular targets. By conditional inactivation of Fgfr1 and Fgfr2 and overexpression of the FGF antagonist sprouty 2 in different cell types, we have dissected the role of FGF signaling during heart outflow tract development in mouse. Contrary to expectation, cardiac neural crest and endothelial cells are not primary paracrine targets. FGF signaling within second heart field mesoderm is required for remodeling of the outflow tract: when disrupted, outflow myocardium fails to produce extracellular matrix and TGFbeta and BMP signals essential for endothelial cell transformation and invasion of cardiac neural crest. We conclude that an autocrine regulatory loop, initiated by the reception of FGF signals by the mesoderm, regulates correct morphogenesis at the arterial pole of the heart. These findings provide new insight into how FGF signaling regulates context-dependent cellular responses during development. | 18,832,392 |
Frs2alpha-deficiency in cardiac progenitors disrupts a subset of FGF signals required for outflow tract morphogenesis. | The cardiac outflow tract (OFT) is a developmentally complex structure derived from multiple lineages and is often defective in human congenital anomalies. Although emerging evidence shows that fibroblast growth factor (FGF) is essential for OFT development, the downstream pathways mediating FGF signaling in cardiac progenitors remain poorly understood. Here, we report that FRS2alpha (FRS2), an adaptor protein that links FGF receptor kinases to multiple signaling pathways, mediates crucial aspects of FGF-dependent OFT development in mouse. Ablation of Frs2alpha in mesodermal OFT progenitor cells that originate in the second heart field (SHF) affects their expansion into the OFT myocardium, resulting in OFT misalignment and hypoplasia. Moreover, Frs2alpha mutants have defective endothelial-to-mesenchymal transition and neural crest cell recruitment into the OFT cushions, resulting in OFT septation defects. These results provide new insight into the signaling molecules downstream of FGF receptor tyrosine kinases in cardiac progenitors. | 18,832,393 |
Altered expression of TRPV1 and sensitivity to capsaicin in pulmonary myelinated afferents following chronic airway inflammation in the rat. | Vagal pulmonary myelinated afferents are normally not activated by capsaicin, a selective agonist of transient receptor potential vanilloid type 1 (TRPV1) receptors. This study was carried out to investigate whether the expression of TRPV1 in these afferents is altered when chronic airway inflammation is induced by ovalbumin (Ova) sensitization. Two groups of Brown-Norway rats (sensitized and control) were exposed to aerosolized Ova and vehicle, respectively, 3 days per week for 3 weeks. After the C-fibre conduction in both vagus nerves was blocked, right-atrial injection of capsaicin elicited augmented breaths in sensitized rats breathing spontaneously, but not in control rats, indicating a stimulation of rapidly adapting receptors (RARs) by capsaicin. Single-unit fibre activities of RARs and slow adapting receptors (SARs), identified by their firing behaviour and adaptation indexes in response to lung inflation, were recorded in anaesthetized, vagotomized and artificially ventilated rats. Capsaicin injection evoked either negligible or no response in both RARs and SARs of control rats. However, in striking contrast, the same dose of capsaicin evoked an immediate stimulatory effect on these myelinated afferents in sensitized rats. Furthermore, the immunohistochemistry experiments showed that there was a significant increase in the proportion of TRPV1-expressing pulmonary neurones in nodose ganglia of sensitized rats; this increase in TRPV1 expression was found mainly in neurofilament-positive (myelinated) neurones. In conclusion, allergen-induced airway inflammation clearly elevated capsaicin sensitivity in myelinated pulmonary afferents, which probably resulted from an increased expression of TRPV1 in these sensory nerves. | 18,832,423 |
Autonomous initiation and propagation of action potentials in neurons of the subthalamic nucleus. | The activity of the subthalamic nucleus (STN) is intimately related to movement and is generated, in part, by voltage-dependent Na(+) (Na(v)) channels that drive autonomous firing. In order to determine the principles underlying the initiation and propagation of action potentials in STN neurons, 2-photon laser scanning microscopy was used to guide tight-seal whole-cell somatic and loose-seal cell-attached axonal/dendritic patch-clamp recordings and compartment-selective ion channel manipulation in rat brain slices. Action potentials were first detected in a region that corresponded most closely to the unmyelinated axon initial segment, as defined by Golgi and ankyrin G labelling. Following initiation, action potentials propagated reliably into axonal and somatodendritic compartments with conduction velocities of approximately 5 m s(-1) and approximately 0.7 m s(-1), respectively. Action potentials generated by neurons with axons truncated within or beyond the axon initial segment were not significantly different. However, axon initial segment and somatic but not dendritic or more distal axonal application of low [Na(+)] ACSF or the selective Na(v) channel blocker tetrodotoxin consistently depolarized action potential threshold. Finally, somatodendritic but not axonal application of GABA evoked large, rapid inhibitory currents in concordance with electron microscopic analyses, which revealed that the somatodendritic compartment was the principal target of putative inhibitory inputs. Together the data are consistent with the conclusions that in STN neurons the axon initial segment and soma express an excess of Na(v) channels for the generation of autonomous activity, while synaptic activation of somatodendritic GABA(A) receptors regulates the axonal initiation of action potentials. | 18,832,425 |
Hydrogen sulfide inhibits rotenone-induced apoptosis via preservation of mitochondrial function. | Hydrogen sulfide (H(2)S) has been proposed as a novel neuromodulator, which plays critical roles in the central nervous system affecting both neurons and glial cells. However, its relationship with neurodegenerative diseases is unexplored. The present study was undertaken to investigate the effects of H(2)S on cell injury induced by rotenone, a commonly used toxin in establishing in vivo and in vitro Parkinson's disease (PD) models, in human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). We report here that sodium hydrosulfide (NaHS), an H(2)S donor, concentration-dependently suppressed rotenone-induced cellular injury and apoptotic cell death. NaHS also prevented rotenone-induced p38- and c-Jun NH(2)-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) phosphorylation and rotenone-mediated changes in Bcl-2/Bax levels, mitochondrial membrane potential (DeltaPsi(m)) dissipation, cytochrome c release, caspase-9/3 activation and poly(ADP-ribose) polymerase cleavage. Furthermore, 5-hydroxydecanoate, a selective blocker of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, attenuated the protective effects of NaHS against rotenone-induced cell apoptosis. Thus, we demonstrated for the first time that H(2)S inhibited rotenone-induced cell apoptosis via regulation of mitoK(ATP) channel/p38- and JNK-MAPK pathway. Our data suggest that H(2)S may have potential therapeutic value for neurodegenerative diseases, such as PD. | 18,832,435 |
Familial non-medullary thyroid carcinoma displays the features of clinical anticipation suggestive of a distinct biological entity. | Non-medullary thyroid carcinoma (NMTC) is mostly sporadic, but familial clustering is described. We aimed to compare the features of patients with sporadic and familial NMTC (FNMTC) patients and to assess whether FNMTC patients with parent-child relationship exhibit the 'anticipation' phenomenon (earlier age at disease onset and increased severity in successive generations). Among 300 NMTCs followed in the Section of Endocrinology (University of Siena, Italy), 34 (11.3%) patients, all with the papillary histotype, (16 kindred), met the criteria of FNMTC. Twenty-seven of them (79.4%) exhibited a parent-child relationship and seven (20.6%) a sibling relationship. These patients were compared with 235 patients with sporadic papillary thyroid cancer (PTCs). To analyze the features of FNMTC of the first and second generations, we cumulated the series of Siena with 32 additional FNMTC patients (15 kindred) from the Department of Endocrinology-Endocrine Oncology, Thessaloniki, Greece. Significant difference between sporadic PTC and FNMTC patients included more frequent tumor multifocality (P=0.001) and worse final outcome in FNMTC patients (P=0.001). Among 47 FNMTC with parent-child relationship, we found an earlier age at disease presentation (P<0.0001), diagnosis (P<0.0001), and disease onset (P=0.04) in the second generation when compared with the first generation. Patients in the second generation were more frequently males (P=0.02); their tumors were more frequently multifocal (P=0.003) and bilateral (P=0.01), had higher rate of lymph node metastases at surgery (P=0.02) and worse outcome (P=0.04) when compared with the first generation. In conclusion, FNMTC displays the features of clinical 'anticipation' with the second generation acquiring the disease at an earlier age and having more advanced disease at presentation. | 18,832,444 |
KRAS mutations: an old oncogene becomes a new predictive biomarker. | This commentary highlights a novel assay for detection of mutations in KRAS, which have recently emerged as a useful negative predictive biomarker. | 18,832,458 |
Keeping up with the next generation: massively parallel sequencing in clinical diagnostics. | The speed, accuracy, efficiency, and cost-effectiveness of DNA sequencing have been improving continuously since the initial derivation of the technique in the mid-1970s. With the advent of massively parallel sequencing technologies, DNA sequencing costs have been dramatically reduced. No longer is it unthinkable to sequence hundreds or even thousands of genes in a single individual with a suspected genetic disease or complex disease predisposition. Along with the benefits offered by these technologies come a number of challenges that must be addressed before wide-scale sequencing becomes accepted medical practice. Molecular diagnosticians will need to become comfortable with, and gain confidence in, these new platforms, which are based on radically different technologies compared to the standard DNA sequencers in routine use today. Experience will determine whether these instruments are best applied to sequencing versus resequencing. Perhaps most importantly, along with increasing read lengths inevitably comes increased ascertainment of novel sequence variants of uncertain clinical significance, the postanalytical aspects of which could bog down the entire field. But despite these obstacles, and as a direct result of the promises these sequencing advances present, it will likely not be long before next-generation sequencing begins to make an impact in molecular medicine. In this review, technical issues are discussed, in addition to the practical considerations that will need to be addressed as advances push toward personal genome sequencing. | 18,832,462 |
Rapid allelic discrimination by TaqMan PCR for the detection of the Gilbert's syndrome marker UGT1A1*28. | Gilbert's syndrome causes mild, unconjugated hyperbilirubinemia and is present in approximately 10% of the Caucasian population. The basis of the disorder is a 70% reduction in bilirubin glucuronidation catalyzed by the UDP-glucuronosyltransferase 1A1 (UGT1A1), which, in Caucasians, is the result of a homozygous TA insertion into the promoter region of the UGT1A1 gene (UGT1A1*28). Homozygous carriers of UGT1A1*28 as well as those with additional UGT1A variants can suffer from severe irinotecan toxicity or jaundice during treatment with the protease inhibitor atazanavir. UGT1A1*28 genotyping identifies patients at risk for drug toxicity and can increase drug safety by dose individualization. Rapid and facile UGT1A1*28 genotyping is therefore of great clinical importance. Two hundred ninety-one patients with suspected Gilbert's syndrome were genotyped using the TaqMan 5'nuclease assay with minor groove binder-non fluorescent quench probes; results were confirmed by direct sequencing. Ninety-six patients (33%) were homozygous for UGT1A1*28, which was verified by direct sequencing of a different PCR product showing 100% concordance with the TaqMan PCR results. We describe a novel UGT1A1*28 genotyping method that employs allelic discrimination by TaqMan PCR. This assay provides a rapid, high-throughput, and cost-effective method for Gilbert's syndrome genotyping, which is of value for pretreatment screening of potential irinotecan toxicity. The method utilizes a technological platform that is widely used in clinical practice and could therefore be easily adapted for routine clinical applications. | 18,832,463 |
Interplay of beta2* nicotinic receptors and dopamine pathways in the control of spontaneous locomotion. | Acetylcholine (ACh) is a known modulator of the activity of dopaminergic (DAergic) neurons through the stimulation of nicotinic ACh receptors (nAChRs). Yet, the subunit composition and specific location of nAChRs involved in DA-mediated locomotion remain to be established in vivo. Mice lacking the beta2 subunit of nAChRs (beta2KO) display striking hyperactivity in the open field, which suggests an imbalance in DA neurotransmission. Here, we performed the selective gene rescue of functional beta2*-nAChRs in either the substantia nigra pars compacta (SNpc) or the ventral tegmental area (VTA) of beta2KO mice. SNpc rescued mice displayed normalization of locomotor activity, both in familiar and unfamiliar environments, whereas restoration in the VTA only rescued exploratory behavior. These data demonstrate the dissociation between nigrostriatal and mesolimbic beta2*-nAChRs in regulating unique locomotor functions. In addition, the site-directed knock-down of the beta2 subunit in the SNpc by RNA interference caused hyperactivity in wild-type mice. These findings highlight the crucial interplay of nAChRs over the DA control of spontaneous locomotion. | 18,832,468 |
Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. | Glucuronidation via UDP-glucuronosyltransferase (UGT) is an increasingly important clearance pathway. In this study intrinsic clearance (CL(int)) values for buprenorphine, carvedilol, codeine, diclofenac, gemfibrozil, ketoprofen, midazolam, naloxone, raloxifene, and zidovudine were determined in pooled human liver microsomes using the substrate depletion approach. The in vitro clearance data indicated a varying contribution of glucuronidation to the clearance of the compounds studied, ranging from 6 to 79% for midazolam and gemfibrozil, respectively. The CL(int) was obtained using either individual or combined cofactors for cytochrome P450 (P450) and UGT enzymes with alamethicin activation and in the presence and absence of 2% bovine serum albumin (BSA). In the presence of combined P450 and UGT cofactors, CL(int) ranged from 2.8 to 688 microl/min/mg for zidovudine and buprenorphine, respectively; the clearance was approximately equal to the sum of the CL(int) values obtained in the presence of individual cofactors. The unbound intrinsic clearance (CL(int, u)) was scaled to provide an in vivo predicted CL(int); the data obtained in the presence of combined cofactors resulted in 5-fold underprediction on average. Addition of 2% BSA to the incubation with both P450 and UGT cofactors reduced the bias in the clearance prediction, with 8 of 10 compounds predicted within 2-fold of in vivo values with the exception of raloxifene and gemfibrozil. The current study indicates the applicability of combined cofactor conditions in the assessment of clearance for compounds with a differential contribution of P450 and UGT enzymes to their elimination. In addition, improved predictability of microsomal data is observed in the presence of BSA, in particular for UGT2B7 substrates. | 18,832,476 |
Telling interviewers about sexual abuse: predictors of child disclosure at forensic interviews. | This study aims to identify characteristics that predict full disclosure by victims of sexual abuse during a forensic interview. Data came from agency files for 987 cases of sexual abuse between December 2001 and December 2003 from Children's Advocacy Centers (CACs) and comparison communities within four U.S. states. Cases of children fully disclosing abuse when interviewed were compared to cases of children believed to be victims who gave no or partial disclosures. The likelihood of disclosure increased when victims were girls, a primary caregiver was supportive, and a child's disclosure instigated the investigation. The likelihood of disclosure was higher for children who were older at abuse onset and at forensic interview (each age variable having an independent effect). Communities differed on disclosure rate, with no difference associated with having a CAC. Findings suggest factors deserving consideration prior to a forensic interview, including organizational and community factors affecting disclosure rates. | 18,832,489 |
Team negotiation: social, epistemic, economic, and psychological consequences of subgroup conflict. | Large collectives (e.g., organizations, political parties, nations) are seldom unitary players. Rather, they consist of different subgroups that often have conflicting interests. Nonetheless, negotiation research consistently regards negotiating teams, who represent these collectives, as monolithic parties with uniform interests. This article integrates concepts from social psychology, management, political science, and behavioral game theory to explore the effects of subgroup conflict on team negotiation. Specifically, the present research introduced a conflict of interests within negotiating teams and investigated how this internal conflict affects the outcome of the negotiation between teams. An experiment with 80 four-person teams found that conflict between subgroups had a detrimental effect on the performance of negotiating teams. This research also employed a recent model of motivated information processing in groups to investigate possible processes underlying the effect of subgroup conflict on team negotiation. | 18,832,517 |
Long-term outcomes of physician peer teaching. | Research conducted in 10 cities assessed long-term pediatric asthma outcomes from a peer teaching intervention for physicians to improve their asthma-related clinical and counseling skills. Hypotheses were better outcomes for patients, symptom reduction, less health care use, and enhanced view of the physician. Peers trained 53 intervention group pediatricians (seeing 418 patients); 48 pediatricians (seeing 452 patients) were controls. Patients provided baseline and 2-year follow-up data, collected by telephone interview and from medical records. Intent-to-treat analyses used Poisson regression and general estimation equations. Treatment physicians' patients gave them higher performance ratings ( P = .02). Patients had fewer sleep disruptions from asthma symptoms ( P = .03). Those with baseline health care use had fewer ED visits ( P = .005), hospitalizations (P = .03), and urgent office visits (P = .001), and they made fewer phone calls to the doctor's office (P = .02). Treatment physicians spent no more patient visit time than control physicians. Peer training increased patient's positive views of clinician's performance and reduced children's symptoms and health care use up to two years post program. | 18,832,540 |
Short-term outcomes of late preterms: an institutional experience. | This article describes the short-term outcomes of late preterm neonates born between 34 and 36 (6/7) weeks gestational age (GA) in a 4-year period. A total of 1381/ 20554 (6.7%) births were between 34 and 36 weeks of GA and were predominantly Caucasian (87%). In all, 697/1381 (51%) were admitted to nursery whereas 684/1381 (49%) remained with their mothers. Of the babies born at 34, 35, and 36 weeks GA, 97%, 53%, and 32%, respectively, required admission and of these 30%, 33%, and 23%, respectively, required respiratory support. Air leaks developed in <4% infants. Median length of stay and age at full enteral feeds were 11, 6, and 4 days and 10, 6, and 3 days for 34, 35, and 36 weeks GA, respectively. It is concluded that late preterms have significant morbidity in the neonatal period. | 18,832,549 |
De novo mRNA synthesis is required for both consolidation and reconsolidation of fear memories in the amygdala. | Memory consolidation is the process by which newly learned information is stabilized into long-term memory (LTM). Considerable evidence indicates that retrieval of a consolidated memory returns it to a labile state that requires it to be restabilized. Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of the amygdala (LA). We have previously shown that de novo protein synthesis in the LA is required for reconsolidation of auditory fear memories. One key question is whether protein synthesis during reconsolidation depends on already existing mRNAs or on synthesis of new mRNAs in the amygdala. In the present study, we examined the effect of mRNA synthesis inhibition during consolidation and reconsolidation of auditory fear memories. We first show that intra-LA infusion of two different mRNA inhibitors dose-dependently impairs long-term memory but leaves short-term memory (STM) intact. Next, we show that intra-LA infusion of the same inhibitors dose-dependently blocks post-reactivation long-term memory (PR-LTM), whereas post-reactivation short-term memory (PR-STM) is left intact. Furthermore, the same treatment in the absence of memory reactivation has no effect. Together, these results show that both consolidation and reconsolidation of auditory fear memories require de novo mRNA synthesis and are equally sensitive to disruption of de novo mRNA synthesis in the LA. | 18,832,561 |
Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. | Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Molecular determinants of desmoid recurrence remain obscure. beta-Catenin deregulation has been commonly identified in sporadic desmoids although the incidence of CTNNB1 (the gene encoding beta-catenin) mutations is uncertain. Consequently, we evaluated the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoids and examined whether mutation type was relevant to desmoid outcome. Desmoid specimens (195 tumors from 160 patients, 1985 to 2005) and control dermal scars were assembled into a clinical data-linked tissue microarray. CTNNB1 genotyping was performed on a 138-sporadic desmoid subset. Immunohistochemical scoring was performed per standard criteria and data were analyzed using Kaplan-Meier and other indicated methods. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: 41A (59%), 45F (33%), and 45P (8%, excluded from further analysis because of rarity). Five-year recurrence-free survival was significantly poorer in 45F-mutated desmoids (23%, P < 0.0001) versus either 41A (57%) or nonmutated tumors (65%). Nuclear beta-catenin expression was observed in 98% of specimens and intensity was inversely correlated with incidence of desmoid recurrence (P < 0.01). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches. | 18,832,571 |
CGI-58 is an alpha/beta-hydrolase within lipid transporting lamellar granules of differentiated keratinocytes. | CGI-58 is the causative molecule underlying Dorfman-Chanarin syndrome, a neutral lipid storage disease exhibiting apparent clinical features of ichthyosis. CGI-58, associated with triacylglycerol hydrolysis, has an alpha/beta-hydrolase fold and is also known as the alpha/beta-hydrolase domain-containing protein 5. The purpose of this study was to elucidate the function of CGI-58 and the pathogenic mechanisms of ichthyosis in Dorfman-Chanarin syndrome. Using an anti-CGI-58 antibody, we found CGI-58 to be expressed in the upper epidermis, predominantly in the granular layer cells, as well as in neurons and hepatocytes. Immunoelectron microscopy revealed that CGI-58 was also localized to the lamellar granules (LGs), which are lipid transport and secretion granules found in keratinocytes. CGI-58 expression was markedly reduced in the epidermis of patients with harlequin ichthyosis, demonstrating defective LG formation. In cultured keratinocytes, CGI-58 expression was mildly up-regulated under high Ca(2+) conditions and markedly up-regulated in three-dimensional, organotypic cultures. In the developing human epidermis, CGI-58 immunostaining was observed at an estimated gestational age of 49 days, and CGI-58 mRNA expression was up-regulated concomitantly with both epidermal stratification and keratinocyte differentiation. CGI-58 knockdown reduced expression of keratinocyte differentiation/keratinization markers in cultured human keratinocytes. Our results indicate that CGI-58 is expressed and packaged into LGs during keratinization and likely plays crucial role(s) in keratinocyte differentiation and LG lipid metabolism, contributing to skin lipid barrier formation. | 18,832,586 |
A large excess in apparent solar oblateness due to surface magnetism. | The shape of the Sun subtly reflects its rotation and internal flows. The surface rotation rate, approximately 2 kilometers per second at the equator, predicts an oblateness (equator-pole radius difference) of 7.8 milli-arc seconds, or approximately 0.001%. Observations from the Reuven Ramaty High-Energy Solar Spectroscopic Imager satellite show unexpectedly large flattening, relative to the expectation from surface rotation. This excess is dominated by the quadrupole term and gives a total oblateness of 10.77 +/- 0.44 milli-arc seconds. The position of the limb correlates with a sensitive extreme ultraviolet proxy, the 284 angstrom limb brightness. We relate the larger radius values to magnetic elements in the enhanced network and use the correlation to correct for it as a systematic error term in the oblateness measurement. The corrected oblateness of the nonmagnetic Sun is 8.01 +/- 0.14 milli-arc seconds, which is near the value expected from rotation. | 18,832,608 |
Temperature-induced hydrophobic-hydrophilic transition observed by water adsorption. | The properties of nanoconfined and interfacial water in the proximity of hydrophobic surfaces play a pivotal role in a variety of important phenomena such as protein folding. Water inside single-walled carbon nanotubes (SWNTs) can provide an ideal system for investigating such nanoconfined interfacial water on hydrophobic surfaces, provided that the nanotubes can be opened without introducing excess defects. Here, we report a hydrophobic-hydrophilic transition upon cooling from 22 degrees C to 8 degrees C via the observation of water adsorption isotherms in SWNTs measured by nuclear magnetic resonance. A considerable slowdown in molecular reorientation of such adsorbed water was also detected. The observed transition demonstrates that the structure of interfacial water could depend sensitively on temperature, which could lead to intriguing temperature dependences involving interfacial water on hydrophobic surfaces. | 18,832,642 |
Imaging preventable infarction in patients with acute ischemic stroke. | One of the goals of neuroimaging in acute ischemic stroke is to identify those patients whose outcome will be improved by therapeutic intervention. This article will discuss the design, analysis, and interpretation of clinical research studies carried out to establish the accuracy and clinical value of neuroimaging to select such patients. | 18,832,661 |
Cutting edge: Immunity against a "silent" salivary antigen of the Lyme vector Ixodes scapularis impairs its ability to feed. | Ixodes scapularis ticks transmit the Lyme disease agent in the United States. Although strong antitick immunity mediates tick rejection by certain vertebrates, only a few Ags have been molecularly characterized. We show that guinea pig vaccination against a secreted tick salivary immunomodulator, sialostatin L2, can lead to decreased feeding ability of I. scapularis nymphs. Increased rejection rate, prolonged feeding time, and apparent signs of inflammation were observed for nymphs attached to vaccinated animals, indicating a protective host immune response. Interestingly, sialostatin L2 humoral recognition does not take place upon repeated tick exposure in control animals, but only in the vaccinated animals that neutralize sialostatin L2 action. Therefore, we demonstrate an essential sialostatin L2 role upon nymphal infestation that can be blocked by vertebrate immunity and propose the discovery of similarly "silent" Ags toward the development of a multicomponent vaccine that will protect against tick bites and the pathogens they transmit. | 18,832,673 |
Cutting edge: Contact with secondary lymphoid organs drives postthymic T cell maturation. | T cell development, originally thought to be completed in the thymus, has recently been shown to continue for several weeks in the lymphoid periphery. The forces that drive this peripheral maturation are unclear. The use of mice transgenic for GFP driven by the RAG2 promoter has enabled the ready identification and analysis of recent thymic emigrants. Here, we show that recent thymic emigrant maturation is a progressive process and is promoted by T cell exit from the thymus. Further, we show that this maturation occurs within secondary lymphoid organs and does not require extensive lymphocyte recirculation. | 18,832,674 |
CD4 T cell-mediated rejection of cardiac allografts in B cell-deficient mice. | CD4 T cell-dependent mechanisms promoting allograft rejection include expression of inflammatory functions within the graft and the provision of help for donor-reactive CD8 T cell and Ab responses. These studies tested CD4 T cell-mediated rejection of MHC-mismatched cardiac allografts in the absence of both CD8 T and B lymphocytes. Whereas wild-type C57BL/6 recipients depleted of CD8 T cells rejected A/J cardiac grafts within 10 days, allografts were not rejected in B cell-deficient B6.muMT(-/-) recipients depleted of CD8 T cells. Isolated wild-type C57BL/6 and B6.muMT(-/-) CD4 T cells had nearly equivalent in vivo alloreactive proliferative responses. CD4 T cell numbers in B6.muMT(-/-) spleens were 10% of that in wild-type mice but were only slightly decreased in peripheral lymph nodes. CD8 T cell depletion did not abrogate B6.muMT(-/-) mice rejection of A/J skin allografts and this rejection rendered these recipients able to reject A/J cardiac allografts. Redirection of the alloimmune response to the lymph nodes by splenectomy conferred the ability of B6.muMT(-/-) CD4 T cells to reject cardiac allografts. These results indicate that the low number of splenic CD4 T cells in B6.muMT(-/-) mice underlies the inability to reject cardiac allografts and this inability is overcome by diverting the CD4 T cell response to the peripheral lymph nodes. | 18,832,680 |
Splenic phagocytes promote responses to nucleosomes in (NZB x NZW) F1 mice. | Autoantigen presentation to T cells is crucial for the development of autoimmune disease. However, the mechanisms of autoantigen presentation are poorly understood. In this study, we show that splenic phagocytes play an important role in autoantigen presentation in murine lupus. Nucleosomes are major autoantigens in systemic lupus erythematosus. We found that nucleosome-specific T cells were stimulated dominantly in the spleen, compared with lymph nodes, lung, and thymus. Among splenic APCs, F4/80(+) macrophages and CD11b(+)CD11c(+) dendritic cells were strong stimulators for nucleosome-specific T cells. When splenic phagocytes were depleted in (NZB x NZW) F(1) (NZB/W F(1)) mice, nucleosome presentation in the spleen was dramatically suppressed. Moreover, depletion of splenic phagocytes significantly suppressed anti-nucleosome Ab and anti-dsDNA Ab production. Proteinuria progression was delayed and survival was prolonged in phagocyte-depleted mice. The numbers of autoantibody- secreting cells were decreased in the spleen from phagocyte-depleted mice. Multiple injections of splenic F4/80(+) macrophages, not those of splenic CD11c(+) dendritic cells, induced autoantibody production and proteinuria progression in NZB/W F(1) mice. These results indicate that autoantigen presentation by splenic phagocytes including macrophages significantly contributes to autoantibody production and disease progression in lupus-prone mice. | 18,832,681 |
Cyclooxygenase inhibition during allergic sensitization increases STAT6-independent primary and memory Th2 responses. | Immune sensitization and memory generation are required for the development of allergic inflammation. Our previous studies demonstrate that the cyclooxygenase (COX) metabolic pathway is actively involved in allergic responses and COX inhibition increases allergic airway inflammation in a STAT6-independent fashion. To test the hypothesis that COX inhibition augments allergic inflammation by enhancing immune sensitization and memory, we sensitized STAT6 knockout mice with an i.p. injection of OVA with aluminum hydroxide as an adjuvant and treated the mice with the COX inhibitor indomethacin or vehicle for analyses of the primary and memory immune responses. We found that COX inhibition during immune sensitization, but not the allergic challenge phase, was necessary and sufficient to increase allergic inflammation. COX inhibition during sensitization increased the numbers of mature dendritic cells and activated CD4 T cells in the spleen and augmented OVA-specific IL-5 and IL-13 responses of the splenic CD4 T cells at day 5 after sensitization. COX inhibition during sensitization also augmented allergic Th2 response to OVA challenge 90 days after the sensitization. Therefore, COX inhibition during allergic sensitization augments allergic responses by enhancing Th2 cell activation and memory generation and the proallergic effect is STAT6-independent. These findings provide a mechanistic explanation for the increased allergic inflammation previously shown in the mice treated with COX inhibitors and in COX-deficient mice and suggest that use of COX-inhibiting drugs during initial allergen exposure may increase the risk of developing allergic responses. | 18,832,692 |
XCL1 enhances regulatory activities of CD4+ CD25(high) CD127(low/-) T cells in human allergic asthma. | Chemokine-mediated recruitment of regulatory cell subsets to the airway during inflammation and enhancement of their activities are potential strategies for therapeutic development in allergic asthma (AA). In this study, we aim to explore the role of XCL1, a chemokine associated with immune suppression and allergy, on CD4(+)CD25(high)CD127(low/-) regulatory T cell (Treg) function in AA. Flow cytometry and PCR analysis showed a reduction in XCL1 and XCR1 expression in AA Treg compared with healthy control and nonallergic asthmatic counterparts. This reduction in XCL1 expression was associated with the suboptimal regulatory function of Treg in AA. Interestingly, incubation with recombinant human XCL1 significantly increased Treg-mediated suppression and cytotoxicity by up-regulating expression of XCL1 and chief effector molecules of Treg function. Altogether, these results suggest an association between dysregulated XCL1 expression and reduced Treg activities in AA, as well as a potential role of XCL1 in reversing defective Treg function in the disease. | 18,832,695 |
NKG2D is critical for NK cell activation in host defense against Pseudomonas aeruginosa respiratory infection. | Pseudomonas aeruginosa is a major cause of nosocomial respiratory infections. The eradication of P. aeruginosa from the lung involves the orchestrated actions of the pulmonary epithelium and both resident and recruited immune cells. The NKG2D receptor is constitutively expressed on the surface of circulating and tissue-resident NK cells (and other cytotoxic lymphocytes), and is capable of controlling NK cell activation and production of cytokines, such as IFN-gamma via interactions with ligands expressed on the surface of stressed cells. Previously, we demonstrated that NKG2D mediates pulmonary clearance of P. aeruginosa. In the present study, we investigated the cellular and molecular mechanisms of NKG2D-mediated clearance of P. aeruginosa using a novel transgenic mouse model of doxycycline-inducible conditional expression of NKG2D ligands (retinoic acid early transcript 1, alpha) in pulmonary epithelial cells. NKG2D ligand expression in this model increased pulmonary clearance, cellular phagocytosis, and survival following P. aeruginosa respiratory infection. Additionally, NK cell sensitivity to ex vivo LPS stimulation was greater in lung cells isolated from naive transgenic mice administered doxycycline. We also showed that NK cells are the primary source of lymphocyte-derived IFN-gamma in response to P. aeruginosa respiratory infection. Significantly, we demonstrated that NKG2D is critical to the nonredundant IFN-gamma production by pulmonary NK cells following acute P. aeruginosa infection. These results represent the principal report of NKG2D-mediated activation of lung NK cells following respiratory infection with an opportunistic pathogen and further establish the importance of NKG2D in the host response against P. aeruginosa respiratory infection. | 18,832,705 |
Rap1 activation is required for Fc gamma receptor-dependent phagocytosis. | Phagocytosis of IgG-opsonized microbes via the Fc gamma receptor (Fc gammaR) requires the precise coordination of a number of signaling molecules, including the low-molecular mass GTPases. Little is known about the Ras-family GTPase Rap1 in this process. We therefore investigated its importance in mediating Fc gammaR-dependent phagocytosis in NR8383 rat alveolar macrophages. Pulldown of active Rap1 and fluorescence microscopic analysis of GFP-RalGDS (Ral guanine dissociation stimulator)-transfected macrophages revealed that Rap1 is indeed activated by Fc gammaR crosslinking. Inhibition of Rap1 activity, both by Rap1GAP (GTPase-activating protein) expression and liposome-delivered blocking Ab, severely impaired the ability of cells to ingest IgG-opsonized targets. Fc gammaR-induced Rap1 activation was found to be independent of both cAMP and Ca(2+), suggesting a role for the second messenger-independent guanosine exchange factor, C3G. This was supported by the facts that 1) liposome-delivered blocking Ab against C3G inhibited both Fc gammaR-dependent phagocytosis and Rap1 activation, and 2) both active Rap1GTP and C3G were found to translocate to the phagosome. Taken together, our data demonstrate a novel role for Rap1 and its exchange factor C3G in mediating Fc gammaR-dependent phagocytosis. | 18,832,707 |
Inhibition of IFN-gamma-induced STAT1 tyrosine phosphorylation by human CMV is mediated by SHP2. | Human CMV (HCMV) is a ubiquitous beta-herpesvirus which has developed several mechanisms of escape from the immune system. IFN-gamma-induced signaling relies on the integrity of the JAK/STAT pathway which is regulated by phosphorylation steps and leads to nuclear translocation of tyrosine-phosphorylated STAT1 (STAT1-P-Tyr), and its binding to IFN-gamma activation site sequences of IFN-gamma-inducible promoters. Activation of those promoters leads to the expression of genes involved in the immune response and in the antiviral effects of IFN-gamma. Src homology region 2 domain-containing phosphatase 2 (SHP2) is a ubiquitous phosphatase involved in the regulation of IFN-gamma-mediated tyrosine phosphorylation. Several mechanisms account for the inhibition IFN-gamma signaling pathway by HCMV. In this study, we have identified a new mechanism that involved the inhibition of STAT1 tyrosine phosphorylation within 12-24 h postinfection. This defect was dependent on HCMV transcription. Consequences were impaired nuclear translocation of STAT1-P-Tyr, inhibition of IFN-gamma activation site-STAT1 interaction, and inhibition of HLA-DR expression. Expression of indoleamine-2,3-dioxygenase which is involved in the antiviral effects of IFN-gamma was also inhibited. Treatment of cells with sodium orthovanadate rescued STAT1 tyrosine phosphorylation, suggesting that a tyrosine phosphatase was involved in this inhibition. Coimmunoprecipitation of STAT1 and SHP2 was induced by HCMV infection, and SHP2 small interfering RNA restored the expression of STAT1-P-Tyr. Our data suggest that SHP2 activation induced by HCMV infection is responsible for the down-regulation of IFN-gamma-induced STAT1 tyrosine phosphorylation. | 18,832,710 |
Stat4 isoforms differentially regulate inflammation and demyelination in experimental allergic encephalomyelitis. | Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model of multiple sclerosis. Signal transducer and activator of transcription 4 (Stat4) is a transcription factor activated by IL-12 and IL-23, two cytokines known to play important roles in the pathogenesis of EAE by inducing T cells to secrete IFN-gamma and IL-17, respectively. We and others have previously shown that therapeutic intervention or targeted disruption of Stat4 was effective in ameliorating EAE. Recently, a splice variant of Stat4 termed Stat4beta has been characterized that lacks 44 amino acids at the C terminus of the full-length Stat4alpha. In this study we examined whether T cells expressing either isoform could affect the pathogenesis of EAE. We found that transgenic mice expressing Stat4beta on a Stat4-deficient background develop an exacerbated EAE compared with wild-type mice following immunization with myelin oligodendrocyte glycoprotein peptide 35-55, while Stat4alpha transgenic mice have greatly attenuated disease. The differential development of EAE in transgenic mice correlates with increased IFN-gamma and IL-17 in Stat4beta-expressing cells in situ, contrasting increased IL-10 production by Stat4alpha-expressing cells. This study demonstrates that Stat4 isoforms differentially regulate inflammatory cytokines in association with distinct effects on the onset and severity of EAE. | 18,832,727 |
The angiogenic response of the aorta to injury and inflammatory cytokines requires macrophages. | The purpose of this study was to define early events during the angiogenic response of the aortic wall to injury. Rat aortic rings produced neovessels in collagen culture but lost this capacity over time. These quiescent rings responded to vascular endothelial growth factor but not to a mixture of macrophage-stimulatory cytokines and chemokines that was angiogenically active on fresh rings. Analysis of cytokine receptor expression revealed selective loss in quiescent rings of the proangiogenic chemokine receptor CXCR2, which was expressed predominantly in aortic macrophages. Pharmacologic inhibition of CXCR2 impaired angiogenesis from fresh rings but had no effect on vascular endothelial growth factor-induced angiogenesis from quiescent explants. Angiogenesis was also impaired in cultures of aortic rings from CXCR2-deficient mice. Reduced CXCR2 expression in quiescent rat aortic rings correlated with marked macrophage depletion. Pharmacologic ablation of macrophages from aortic explants blocked formation of neovessels in vitro and reduced aortic ring-induced angiogenesis in vivo. The angiogenic response of macrophage-depleted rings was completely restored by adding exogenous macrophages. Moreover, angiogenesis from fresh rings was promoted by macrophage CSF (CSF-1) and inhibited with anti-CSF-1 Ab. Thus, aortic angiogenic sprouting following injury is strongly influenced by conditions that modulate resident macrophage numbers and function. | 18,832,730 |
Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood-brain barrier permeability and granulocyte recruitment. | Autoantibody neuromyelitis optica-IgG (NMO-IgG) recognizing aquaporin-4 (AQP4) is implicated as playing a central role in the physiopathology of NMO. The aim of this in vitro-based study was to characterize functional consequences of interaction between NMO-IgG and cells of the neurovascular unit (astrocytes and brain endothelium) that would provide insight into recognized features of NMO, namely altered blood-brain barrier (BBB) permeability and granulocyte recruitment. We used sera from NMO and longitudinally extensive transverse myelitis cases shown to bind in a characteristic perivascular pattern to primate cerebellar slices. Using flow cytometry, we found that sera from NMO-IgG-positive patients reacted with CNS-derived human fetal astrocytes, whereas sera from multiple sclerosis patients did not. We demonstrated that NMO-IgG binding to astrocytes alters aquaporin-4 polarized expression and increases permeability of a human BBB endothelium/astrocyte barrier. We further demonstrated that NMO-IgG binding to human fetal astrocytes can result in NK cell degranulation, astrocyte killing by Ab-dependent cellular cytotoxicity and complement-dependent granulocyte attraction through the BBB model. Our study highlights important functional roles for NMO-IgG that could account for pathological lesions and BBB dysfunction observed in NMO. | 18,832,732 |
Anti-type V collagen humoral immunity in lung transplant primary graft dysfunction. | Primary graft dysfunction (PGD) is a major complication following lung transplantation. We reported that anti-type V collagen (col(V)) T cell immunity was strongly associated with PGD. However, the role of preformed anti-col(V) Abs and their potential target in PGD are unknown. Col(V) immune serum, purified IgG or B cells from col(V) immune rats were transferred to WKY rat lung isograft recipients followed by assessments of lung pathology, cytokines, and PaO(2)/FiO(2), an index of lung dysfunction in PGD. Immune serum, purified IgG, and B cells all induced pathology consistent with PGD within 4 days posttransfer; up-regulated IFN-gamma, TNF-alpha, and IL-1beta locally; and induced significant reductions in PaO(2)/FiO(2). Depleting anti-col(V) Abs before transfer demonstrated that IgG2c was a major subtype mediating injury. Confocal microscopy revealed strong apical col(V) expression on lung epithelial, but not endothelial cells; which was consistent with the ability of col(V) immune serum to induce complement-dependent cytotoxicity only in the epithelial cells. Examination of plasma from patients with or without PGD revealed that higher levels of preformed anti-col(V) Abs were strongly associated with PGD development. This study demonstrates a major role for anti-col(V) humoral immunity in PGD, and identifies the airway epithelium as a target in PGD. | 18,832,733 |
Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase. | Obstructive sleep apnea leads to chronic intermittent hypoxia (CIH) and is associated with atherosclerosis. We have previously shown that C57BL/6J mice exposed to CIH and a high-cholesterol diet develop dyslipidemia, atherosclerosis of the aorta, and upregulation of a hepatic enzyme of lipoprotein secretion, stearoyl coenzyme A desaturase 1 (SCD-1). We hypothesized that (1) SCD-1 deficiency will prevent dyslipidemia and atherosclerosis during CIH; and (2) human OSA is associated with dyslipidemia and upregulation of hepatic SCD. C57BL/6J mice were exposed to CIH or normoxia for 10 weeks while being treated with either SCD-1 or control antisense oligonucleotides. Obese human subjects underwent sleep study and bariatric surgery with intraoperative liver biopsy. In mice, hypoxia increased hepatic SCD-1 and plasma very-low-density lipoprotein cholesterol levels and induced atherosclerosis lesions in the ascending aorta (the cross-section area of 156514+/-57408 microm(2)), and descending aorta (7.0+/-1.2% of the total aortic surface). In mice exposed to CIH and treated with SCD-1 antisense oligonucleotides, dyslipidemia and atherosclerosis in the ascending aorta were abolished, whereas lesions in the descending aorta showed 56% reduction. None of the mice exposed to normoxia developed atherosclerosis. In human subjects, hepatic SCD mRNA levels correlated with the degree of nocturnal hypoxemia (r=0.68, P=0.001). Patients exhibiting oxyhemoglobin desaturations at night showed higher plasma triglyceride and low-density lipoprotein cholesterol levels, compared to subjects without hypoxemia. In conclusion, CIH is associated with dyslipidemia and overexpression of hepatic SCD in both humans and mice alike; SCD-1 deficiency attenuates CIH-induced dyslipidemia and atherosclerosis in mice. | 18,832,746 |
Enhancement of glucose toxicity by hyperbaric oxygen exposure in diabetic rats. | The side effects of hyperbaric oxygen (HBO) treatment, such as oxidative stress and oxygen toxicity, have long been of interest. However, there are no comprehensive studies evaluating such toxic effects in diabetes mellitus (DM). The purpose of this study was to determine the effects of HBO on glucose homeostasis and histological changes in pancreatic beta-cells of experimentally induced diabetic rats. A total of 24 male Wistar rats were randomly divided into 4 groups: 1) Control group, no diabetic induction without HBO treatment; 2) HBO group, exposed to 100% oxygen at 2.8 ATA (atmosphere absolute) for 2 h once daily, for 7 days; 3) DM group, diabetes induced by streptozotocin (STZ) injection; and 4) DM + HBO group, received both STZ injection and HBO exposure. HBO treatment, with clinically recommended pressures and duration of therapy, was started on day 5 after STZ injection, when the blood glucose levels were significantly increased. After the last HBO treatment, the pancreatic tissues were immunostained to measure the areas of insulin immunoreactive beta-cells in the islets of Langerhans. The blood glucose increased significantly following exposure to HBO, with the highest levels achieved in rats, which had been treated with both HBO and diabetic induction. The area populated with insulin immunoreactive beta-cells decreased significantly following diabetic induction and/or HBO exposure, with the smallest area in DM + HBO group. Thus, HBO exposure enhanced the cytotoxic effect of STZ in the beta-cells of the pancreas. HBO should be cautiously employed in diabetic patients. | 18,832,794 |
Growth inhibitory effect of the ternary complex factor Net on human pancreatic carcinoma cell lines. | Pancreatic carcinoma is one of the most aggressive malignancies and carries the most dismal prognoses of all cancers. A better understanding of the genes involving in tumor development may allow us to tackle this rapidly progressive disease. The Net gene belongs to the ternary complex transcription factor (TCF) family and is regulated by the Ras/mitogen-activated protein kinase-signaling pathway. Under basal conditions, Net shows strong repressing function on transcription of proto-oncogene gene c-fos. Moreover, the lower expression of Net has been noted in some carcinoma cells, such as cervical cancer. To study the effect of Net on c-fos expression and its potential role in the growth of pancreatic carcinoma, we developed a recombinant plasmid, a pEGFP-N1-Net, which codes for Net-EGFP fusion proteins, and stably transfected it into BxPC-3 human pancreatic carcinoma cells. Using stable transformants, we were able to show that overexpression of Net decreased the expression of c-fos and inhibited pancreatic cancer cell proliferation. Cell cycle analysis demonstrated that Net overexpression inhibited cell cycle progression. These findings suggested that loss of Net repression could augment c-fos expression and further trigger neoplastic cell proliferation, which was involved in the pathogenesis of pancreatic cancer. Therefore, Net might be a potential target for the treatment of c-fos-positive pancreatic cancer. | 18,832,796 |
Fluoride concentration in dentin of exfoliated primary teeth as a biomarker for cumulative fluoride exposure. | A biomarker for lifetime fluoride exposure would facilitate population-based research and policy making but currently does not exist. This study examined the suitability of primary tooth dentin as a biomarker by comparing dentin fluoride concentration and fluoride exposures. Ninety-nine children's exfoliated primary teeth were collected from 2 fluoridated and 2 fluoride-deficient communities in North Carolina. Coronal dentin was isolated by microdissection and fluoride concentration assayed using the microdiffusion, ion-specific electrode technique. Information on children's fluoride exposures since birth from drinking water, toothpaste, supplements, rinses, food and beverages was collected by a self-reported questionnaire administered to caregivers. Only a small portion of the variance (10%) in incisor dentin fluoride (mean 792, SD 402 mg/kg) was accounted for by the best linear regression model as evaluated by the adjusted R(2). A moderate portion of the variance (60%) of molar dentin fluoride (mean 768, SD 489 mg/kg) was predicted by dietary fluoride supplement exposures, community of residence, and frequent tea consumption. Results for molars suggest that primary tooth dentin concentration may prove to be a satisfactory biomarker for fluoride exposure. | 18,832,828 |
Gender-specific weight estimation of fetuses between 2,501 and 3,999 g--new regression formulae. | To develop new gender-specific regression formulae to estimate fetal weight focusing on a particular weight range from 2,501 to 3,999 g. 3,254 singleton pregnancies were included to generate new regression formulae for female and male fetuses, and to evaluate their accuracy. In comparison with commonly used formulae, the new gender-specific and weight-range-specific method of fetal weight estimation provided greater accuracy. The mean absolute error was less than 7%. When properly used, the new formulae can improve the accuracy of weight estimations in fetuses between 2,501 and 3,999 g. | 18,832,848 |
Single large inguinal lymph node metastasis in human papillomavirus-induced early invasive vulvar cancer of the anterior fourchette in two young women. | The incidence of human papillomavirus (HPV)-induced vulvar cancer in young women is increasing and often presents as microinvasive or early invasive tumors in a grade 3 vulvar intraepithelial neoplasia. So far, the risk of lymph node metastases in early invasive vulvar carcinoma (depth of invasion 1.1-2.0 mm) is reported to be less than 8%. We present 2 cases of young women with early invasive vulvar cancers (depth of invasion 1.5 and 2.0 mm) induced by HPV 16 and 42. In both cases, the cancers are located between the clitoris and urethra and are each accompanied by one groin macro-metastatic lymph node. This case report highlights the necessity for complete inguinofemoral lymphadenectomy and/or adequate radiation therapy of the groin in early invasive tumors in young women to prevent cancer recurrence in the groin. Additionally, the indication for a sentinel node procedure in these specific cases requires particular caution. | 18,832,852 |
Association of A/G polymorphism in intron 13 of the monoamine oxidase B gene with schizophrenia in a Spanish population. | Monoamine oxidase B (MAO-B) enzyme is involved in the oxidative metabolism of dopamine. We studied whether the A644G polymorphism in intron 13 of the MAO-B gene is a risk factor for schizophrenia. 242 subjects diagnosed with schizophrenia and related disorders and 290 hospital-based controls participated in the study. Genomic DNA was isolated from whole blood and genotyped with the allele-specific oligonucleotide polymerase chain reaction method. This polymorphism was studied by diagnosis subgroups and the G allele was identified as a risk factor for developing schizophrenia (p = 0.006). When we performed a sex-specific analysis, the G allele was only a risk factor for developing schizophrenia in women (p = 0.01). Although the frequency of the G allele is higher in male patients than in male controls, no statistically significant association with schizophrenia was found. Our results support the involvement of the MAO-B gene in schizophrenia, particularly in women. | 18,832,861 |
Protection against dryness of facial skin: a rational approach. | Facial skin is unique in that it gets far more exposure to the external environment than skin on other areas of the body and paradoxically, because it contains the thinnest epidermis and stratum corneum, especially on the eye lid. Environmental attacks contribute to drying of facial skin and damage to the stratum corneum. In recent years, there has been an explosion of new products that contain ingredients that claim to benefit facial skin and protect against environmental damage. This review critically examines the scientific basis, rationale and evidence for inclusion of these ingredients in products for protection of facial skin. | 18,832,866 |
The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. | Cases of renal dysfunction in patients receiving tenofovir disoproxil fumarate (TDF) have been reported. We analyzed the renal safety of TDF compared with thymidine analogue-containing (control) regimens through 144 weeks from two clinical trials in antiretroviral-naive HIV-infected patients. We evaluated the changes in renal parameters in 1111 patients (TDF, n = 556; control, n = 555) who were enrolled in two randomized, controlled trials (Studies 903 and 934) comparing TDF vs. either stavudine or zidovudine in combination with efavirenz and either lamivudine or emtricitabine. The studies included patients with serum creatinine less than 1.5 mg/dl, serum phosphorus at least 2.2 mg/dl and estimated glomerular filtration rate by Cockcroft-Gault at least 60 and at least 50 ml/min at screening. Baseline characteristics were similar between groups. No patient discontinued due to renal abnormalities in the TDF arm. Through 144 weeks, the proportion of patients who experienced confirmed abnormalities in serum creatinine (>1.5 mg/dl) or serum phosphorus (<2.0 mg/dl) was less than 1% in both groups; a similar proportion of patients experienced urine proteinuria at least 100 mg/dl (TDF, 5%; control, 6%). The median change from baseline to week 144 in glomerular filtration rate was -2 and 3 ml/min by Cockcroft-Gault, and -2 and -1 ml/min per 1.73 m by modification of diet in renal disease in the TDF and control groups (P < 0.05), respectively. In two randomized, controlled trials, small differences in glomerular filtration rate over time were noted but no clinically relevant renal disease or adverse events were demonstrated in antiretroviral-naive patients treated with TDF through 144 weeks. Additional studies on renal health and renal safety in HIV are important goals for future clinical trials. | 18,832,879 |
The therapeutic phase I trial of the recombinant native HIV-1 Tat protein. | The native HIV-1 Tat protein was chosen as a vaccine candidate based on its key role in the virus life cycle and on the correlation of Tat-specific immune responses with the asymptomatic stage and lower disease progression rates, but also due to its sequence conservation amongst the various HIV clades as well as the adjuvant effects on dendritic cells. Safety, immunogenicity and efficacy data in monkeys support the development of this vaccine concept. | 18,832,884 |
Antigenic mimicry of the HIV envelope by AIDS-associated pathogens. | Only one broadly neutralizing anti-HIV antibody, 2G12, recognises the envelope sugars of HIV. In the present study, we show that 2G12 also recognises Candida albicans and Candida tropicalis with high affinity (11 nmol/l) through a carbohydrate-dependent interaction (50% inhibitory concentration for D-fructose, 12 mmol/l). This is the first report of a neutralizing HIV antibody displaying cross-reactivity with another pathogen, revealing that the carbohydrate neutralization determinant of HIV, defined by 2G12, is more widespread amongst immunogenic, microbial surfaces than previously recognized. | 18,832,887 |
Correlation of vascular endothelial growth factor with the severity of thalassemia intermedia. | Several lines of evidence indicate that thalassemia intermedia is associated with disturbances in vascular endothelial cell proliferation. In addition, autopsy studies of thalassemia intermedia reported obstructive lesions in the pulmonary artery in 44% of cases, especially splenectomized patients, and a recent in-vivo study reported increased level of vascular endothelial growth factor (VEGF) in thalassemia intermedia. The aim of the present study was to determine whether VEGF levels are correlated with the severity of the disease. Blood samples were collected from 21 patients with thalassemia intermedia and assayed for VEGF by a two-site enzyme-linked immunosorbent assay. A significant correlation was noted between VEGF levels and patient age (P = 0.0022, r = 0.82), presence of splenomegaly (P = 0.004, r = 0.79) and hepatomegaly (P = 0.023, r = 0.82). VEGF levels were also significantly correlated with both left ventricular end-diastolic diameter and left ventricular end-systolic diameter (P = 0.02, r = 0.84 and P = 0.01, r = 0.86, respectively). The study indicates that VEGF levels may be related to the clinical severity of thalassemia intermedia, as expressed by the degree of hepatomegaly and splenectomy and cardiac indexes. Further and larger studies are needed to confirm these observations. | 18,832,899 |
Protein S deposition at placenta: a possible role of protein S other than anticoagulation. | Protein S is an antithrombotic cofactor for protein C that also has multifunctional anti-inflammatory, cellular protective, apoptotic and mitogenic properties. Protein S levels are thought to decrease during pregnancy, but the underlying mechanism remains unknown. We compared protein S concentrations throughout normal pregnancy with those of nonpregnant women and measured plasma C4b-binding protein levels in nonpregnant women and in pregnant women at the 40th gestational week. We also examined protein S and C4b-binding protein in the placenta by immunohistochemical staining at early (20th gestational week) and late (40th gestational week) stages of pregnancy. Plasma protein S activity and free protein S-antigen levels significantly decreased from the 10th gestational week and total protein S antigen decreased from the 20th. C4b-binding protein levels between pregnant and nonpregnant women did not significantly differ. The stainable portion of protein S was located at the fetomaternal interface, particularly at degenerative villi. C4b-binding protein was weakly stained at the same areas as protein S. Neither protein S nor C4b-binding protein were stained at normal villi. These results indicated that protein S can protect or restore damaged villi via a physiological effect in addition to its anticoagulation properties. | 18,832,905 |
New advances in hematopoietic cell transplantation. | The present review highlights sentinel work published since 2006 on the definition of the transplantation barrier and the elucidation of cytokine and immune response gene variation in defining posttransplant risks. Recent work has defined the relative importance of matching for the classical human leukocyte antigen (HLA) HLA-A, HLA-B, HLA-C, DRB1, DQB1 genes, and the importance of additive effects of multilocus disparity. This work provides a new framework for donor identification and extends the use of single locus HLA-DQB1 mismatched donors without compromising the success of the transplant. New data demonstrate that permissible class I mismatches may be defined by donor-recipient mismatching at certain residues. The concept that the extended HLA haplotype carries undetected but functional variation provides an approach for mapping novel transplantation determinants, and a means to further improve the clinical results of transplantation from HLA-matched unrelated donors. Finally, the role of sequence variation in immune response and cytokine genes provides a means for assessing risks for a given transplant recipient and may aid in the planning of the transplant procedure. Optimizing the results of unrelated donor transplantation requires an understanding of risks associated with variation of HLA genes within the major histocompatibility complex, and of genes that participate in the immune response and inflammatory pathways. | 18,832,924 |
Radioactive iodine (131I) effects on male fertility. | Radiometabolic therapy with radioactive iodine (I) is the standard treatment for differentiated thyroid cancer and is also currently the treatment of choice for Graves' disease in the United States. and in most countries. Men younger than 40 years of age represent about 10% of all radiometabolic treatments. Thus, the question arises whether I therapy is able to induce a damage to the fertility potential. The different effects caused by I therapy employed in cancer and hyperthyroid patients are reviewed. Most articles about the first category of patients show a damage to the germinal epithelium directly related to the cumulative dose delivered. Although the small amounts used in hyperthyroidism are usually well tolerated in terms of sterility risk, the impairment caused by hyperthyroidism per se is probably higher than that caused by I treatment. Young cancer patients, particularly those with node or lung metastases, who will probably undergo repeated treatments should be aware of the potential risks to their fertility. An evaluation of testicular function is thus advisable. When an impairment of fertility potential is already present, the option of freezing semen should be considered. The available studies concerning I therapy in hyperthyroidism suggest that this treatment does not cause a worsening of semen analysis but an amelioration in affected patients. | 18,832,945 |
Follicle-stimulating hormone treatment of male infertility. | Treatment with gonadotrophins is very effective in patients affected by hypogonadotrophic hypogonadism. The success of follicle-stimulating hormone (FSH) treatment in these men has brought the utilization of the same therapy in infertile oligozoospermic patients, aimed at obtaining a quantitative increase in sperm count. FSH plays a crucial role in human reproduction. This physiological role in spermatogenesis has induced various attempts to treat idiopathic oligozoospermic men with FSH, often inducing the restoration of normal spermatogenesis and spontaneous pregnancy. However, the results obtained so far are still controversial. In this research, attention is focused on the possible criteria able to predict a seminal response to the specific hormonal treatment. Moreover, we have correlated different polymorphisms of FSH receptor gene with the outcome of FSH treatment. In this article, the literature is reviewed, and the authors' experience on using FSH treatment in oligozoospermic patients is discussed. FSH treatment may represent a valid tool for infertile men. However, it should be performed on selected patients utilizing some predictive parameters able to identify a priori responder patients with high probability. | 18,832,946 |
An open pilot study of the combination of escitalopram and bupropion-SR for outpatients with major depressive disorder. | Monotherapy with a selective serotonin reuptake inhibitor (SSRI) is the most common initial treatment for major depressive disorder (MDD), but this monotherapy leads to remission in fewer than a third of patients. The combination of the SSRI escitalopram and bupropion-SR is commonly used for treating patients with MDD who have had an inadequate response to antidepressant monotherapy. This pilot study was conducted to evaluate this combination in the treatment of MDD in patients with chronic or recurrent MDD to estimate safety, tolerability, and remission rates. In this study, 51 outpatients with chronic or recurrent non-psychotic MDD were treated with a combination of escitalopram and bupropion-SR for up to 12 weeks. Participants were started on escitalopram at 10 mg/day, and bupropion-SR was then added at week 1, starting at 150 mg/day. The maximum dose of escitalopram was 20 mg/day and the maximum dose of bupropion-SR was 400 mg/day. Rates of response (62%) and remission (50%) at study exit (based on participants for whom at least one post-baseline measure was collected) were significantly higher than is typical for SSRI monotherapy. The level of treatment emergent adverse events was low, and only 3 participants (6%) discontinued treatment due to side effects. The mean maximum dose of escitalopram was 18 mg/day, which was achieved by week 6, and the mean dose at study exit was also 18 mg/day. The mean maximum dose of bupropion-SR was 329 mg/day, which was achieved by week 8, and the mean dose at study exit was 327 mg/day. These results suggest that the combination of escitalopram and bupropion-SR is effective and well tolerated. Further controlled trials comparing this combination with monotherapy are needed. | 18,832,958 |
Normal values of hertel exophthalmometry in children, teenagers, and adults from Tehran, Iran. | The aim of this study was to present normative values of exophthalmometry in Iranian children, teenagers, and adults and find the effect of age, gender, height, weight, and laterality (right vs. left eye) on normal values of protrusion. In a population-based epidemiological study, ocular protrusion values (mm) were measured in 1063 randomly selected (stratified sampling method) normal subjects using the Hertel exophthalmometer. Weight and height were measured in all subjects. There were 462 (43.5%) females and 601 (56.5%) males. The age ranged from 6 to 70 years (mean +/- SD = 20.3 +/- 10.9). Subjects were divided into three age groups (years); children (range: 6 to 12, mean: 9.2 +/- 1.6), teenagers (range: 13 to 19, mean: 15 +/- 1.4), and adults (range: 20 to 70, mean: 31 +/- 7.9). The mean (+/-SD) absolute ocular protrusion value was 14.2 +/- 1.8 in children, 15.2 +/- 1.9 for teenagers, and 14.7 +/- 2.3 for adults. Right and left eye protrusions were well correlated (r = 0.97, p < 0.0005 in children and adults and r = 0.95, p < 0.0005 in teenagers). However, right eye protrusion was significantly more than on the left side (p < 0.0005). Although males had more eye protrusion, the gender difference was not significant except for teenagers. Weight and height did not have a significant effect on eye protrusion. No individual had more than 2 mm of asymmetry (relative eye protrusion). Increasing age had a significant effect on the eye protrusion (r = +0.32 for children, r = +0.13 for teenagers, and r = -0.30 for adults; 0.001 < p < 0.0005). The ocular protrusion was positively correlated with increasing distance between the two lateral orbital rims (base) in all age groups (p < 0.0005). Any eye protrusion of more than 17.8 mm for Iranian children, 19 mm for Iranian teenagers, and 19.3 mm for Iranian adults and relative eye protrusion of more than 2 mm warrants further clinical examination. Age and base value had a significant impact on normal eye protrusion values. | 18,832,980 |
Immune response of human propagated gammadelta-T-cells to neuroblastoma recommend the Vdelta1+ subset for gammadelta-T-cell-based immunotherapy. | Human peripheral gammadelta-T-cells are able to induce cytolysis of neuroblastoma (Nb) tumor cells. Besides innate effector functions against infected cells and tumors, gammadelta-T-cells are involved in T-helper 1/T-helper 2 (TH1/TH2) differentiation of alphabeta-T-cells. However, as different gammadelta-T-cell subsets vary considerably in their functional properties, the aim of the present study was to define repertoires of cytokines, chemokines, and angiogenic factors of in vitro expanded Vdelta1+ and Vdelta2+ T cells in response to Nb. After short-term culture, both subsets released TH1 [interleukin (IL)-2, interferon (IFN)-gamma, IL-12, tumor necrosis factor (TNF)-alpha, TNF-beta)] and TH2 cytokines (IL-4, -5, -6, -10, -13, Vdelta1 also transforming growth factor (TGF)-beta, chemokines (I-309, monocyte chemotactic protein (MCP)-1-3, regulated upon activation, normal T-cell expressed and secreted), ILs (IL-1, -8, -15), cytokines (leptin) as well as angiogenic growth factors [angiogenin (ANG), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), Insulin-like growth factor (IGF)-I]. These molecules were expressed at higher levels in Vdelta2+ than Vdelta1+ T cells. Nb challenge changed protein expression. TH2 cytokine and IFN-gamma release was blocked in both gammadelta-T-cell subsets. In Vdelta2 gammadelta-T-cells, TH1 cytokines were down-regulated and tumor growth-promoting factors (ANG, VEGF, EGF, and IGF-I) were strongly up-regulated. In contrast, Vdelta1+ gammadelta-T-cells stopped the release of tumor-supportive factors and tolerogenic TGF-beta, and strongly up-regulated TNF-alpha, TNF-beta, MCP-1 and -2 and maintained their IL-2 production. In summary, our data show that after being challenged with Nb cells, propagated Vdelta1+ rather than Vdelta2+ T cells support antitumor responses by secretion of proinflammatory cytokines. Furthermore, in contrast to other cell types, Vdelta1+ T cells do not sustain a growth-promoting or tolerogenic microenvironment. These data make Vdelta1+ T cells an ideal candidate for upcoming immunotherapy trials in Nb. | 18,832,998 |
Clinical-scale lentiviral vector transduction of PBL for TCR gene therapy and potential for expression in less-differentiated cells. | In human gene therapy applications, lentiviral vectors may have advantages over gamma-retroviral vectors because of their ability to transduce nondividing cells, their resistance to gene silencing, and a lack of integration site preference. In this study, we used VSV-G pseudotype third generation lentiviral vectors harboring specific antitumor T-cell receptor (TCR) to establish clinical-scale lentiviral transduction of peripheral blood lymphocyte (PBL). Spinoculation (1000g, 32 degrees C for 2 h) in the presence of protamine sulfate represents the most efficient and economical approach to transduce a large number of PBLs compared with RetroNectin-based methods. Up to 20 million cells per well of a 6-well plate were efficiently transduced and underwent an average 50-fold expansion in 2 weeks. TCR transduced PBL-mediated specific antitumor activities including interferon-gamma release and cell lysis. Compared with gamma-retroviral vectors, the TCR transgene could be preferentially expressed on a less-differentiated cell population. | 18,833,004 |
Proposed guidelines for use of dermal and subdermal fillers. | The great variety of injectable substances for esthetic treatments and their many adverse effects evidence the necessity for agreement among the experts who use such substances. The guidelines to be followed should take into consideration the ideal features of a filler, the criteria of choice (anatomic area, type of imperfection), well established procedures, medical-legal issues (medical charts and informed consent), and typical responses of different anatomic areas. | 18,833,061 |
Dendritic cell vaccines in metastasized malignant melanoma. | Dendritic cells as immunotherapeutic agents against malignancies have been applied for over ten years. Proof of principle studies demonstrated immunogenicity of dendritic cells even in patients suffering from advanced malignancies. Clinicians and immunologists early focused on this innovative immunotherapeutic approach in metastasized malignant melanoma--a malignancy so far resisting most traditional oncologic treatment modalities. In this review we summarize the experience obtained of dendritic cell therapy in patients with malignant melanoma and state past, present and future obstacles. So far over 850 melanoma patients in 51 trials have been reported since 1998. Within these trials there exists a vast heterogeneity concerning type of dendritic cell applied, differentiation and maturation of dendritic cells, type of antigen target and nature, application mode, number of cells applied, vaccination intervals in addition to patients treated at various stages of melanoma. A minority of patients developed anticipated autoimmune adverse events in addition to expected immune system activation symptoms such as fever and local site reaction. As only solitary World Health Organization (WHO) grade III or IV adverse events were reported one can state that dendritic cell therapy is safe. Objective clinical responses have repeatedly been observed in a minority of heavily pretreated and far advanced melanoma patients. Future challenges include optimization and standardization of dendritic cell generation and application, addition of synergistic immunomodulatory agents to enhance immunogenicity and block tumor escape and treatment of patients at earlier stages of disease who will benefit from this innovative therapy. | 18,833,080 |
[Brain evoked potentials as correlates of neural dysfunction in the myofascial pain syndrome]. | To study the peculiarities of nervous system functioning in the conditions of nociceptive afferentation from myofascial trigger points in the myofascial pain syndrome (MFPS), 130 patients, 57 men and 73 women, aged from 20 to 55 years, have been examined. A method of somatosensory evoked potentials (SSEP) with recording of amplitudes and latencies of their main components has been used. Two relevant conclusions based on the results of the study have been made: 1) the similar parameters of SSEP components before and after stopping the MFPS have a different neurophysiologic basis; 2) during the treatment, several variants of changes of SSEP parameters reflecting the interaction of different neurophysiological mechanisms can be found. | 18,833,107 |
[Cognitive evoked potentials in panic disorders]. | Sixteen healthy people and 79 patients with panic disorders (PD), including 50 patients with neurosis (ICD-10 F40-41), 18 with personality disorder (F60) and 11 with schizotypal disorder (F21) have been studied. The main investigation method is recording of cognitive evoked potentials (P300 parameters). Mental and neuropsychological status of patients has been assessed as well. Despite the common clinical presentations of PD, peculiarities of evoked potentials reflecting sensory, activation and cognitive processes in different group of patients are revealed. The reduction of activation processes is observed in patients with neurosis and personality disorder combined with emotional instability in the latter ones. The increase of latency in response to non-target stimuli (a sensory component) is shown in schizotypal patients, the latter may be related to the decrease of activation of frontal-central brain areas. | 18,833,108 |
[Changes of the level of serum antibodies to neuroantigens in patients with schizophrenia during the treatment]. | The level of antibodies (AT) to neuroantigens (nerve growth factor and basic myelin protein) has been studied in the serum of 80 patients with schizophrenia, attack-like type, (ICD-10 items F20.01-02) during the treatment with psychotropic drugs. Therapeutic effectiveness has been measured clinically and with the PANSS. It has been shown that the autoimmune component is present during the acute episode of schizophrenia in about 30% of cases. No statistically significant differences have been found in the mean values of AT before and after the treatment however the dynamics of their changes has been closely related with the results of therapy: the decrease of AT level during the therapy is a predictive factor for good therapeutical remission; on the contrary, the increase of this level may be considered as an unfavorable prognostic factor. | 18,833,110 |
[How to raise efficacy of myringoplasty in extensive defects]. | A comparative trial of miringoplasty efficacy with or without application of biosynthetic wound cover Biocom-1 was performed in 82 patients with sub- and total chronic defects or acute traumatic rupture of the tympanic membrane (58 and 24 patients, respectively). Better clinico-morphological and functional results were achieved in patients treated with application of Biocom-1 (p<0.05). Their stay in hospital was also shorter. Biocom-1 not only provides stable position of the neotympanic membrane but also protects against secondary infection. | 18,833,123 |
[Histamine releasing and immunomodulating activity of dental restorative materials]. | Histamine releasing and immunomodulating activity of the following dental restorative materials (DRM) - Prizmafil, Filtek Z250, XRV Herculite Prodigy, Glasiosite, Te-Econol, Valux Plus, Polofil Supra were studied. It was shown that DRM under study as a rule did not possess the ability to release histamine (H) from human blood basophile (BB) excluding Filtek Z250 which release H from BB in patients with allergy and sound donors. The studied DRM implanted under mouse skin were able to modulate immune response to the allergen, at that some of them increased antibodies of IgE-class forming and other suppressed immune response caused by IgG-antibody forming. Received data have certain significance in the scheme of safety evaluation and individual assessment of DRM having acceptable biocompatibility for specific patient. | 18,833,129 |
[Experimental study of the effectiveness of indirect electrochemical blood oxidation and antioxidant therapy in the treatment of infectious soft tissue wounds]. | In experiments on rats in the process of soft tissues festering wounds treatment there was substantiated the inclusion of 0.03% sodium hypochlorite and antioxidant <<Recsod>> into basic therapy schedule. These preparations inclusion let reduce antioxidant stress and endogenous intoxication levels and eliminate disbalance in antioxidant systems of red blood cells and of organism as a whole in the acute phase of inflammation and speed up wound heeling processes. | 18,833,131 |
[State of local immunity in patients with chronic generalized parodontitis]. | The aim of this work was the determination of the state of local immunity in periodontal complex in patients with chronic generalized periodontitis (CGP). 96 individuals were examined (mean age 43.6+/-1.2 years). All the patients were divided into 2 groups: basic group with CGP patients (76 persons) and comparative group - individuals with intact periodontium (20 persons). To evaluate local immunity in dentogingival fluids the determination of concentrations of IgG, IgM, and IgA immunoglobulins has been used, as well as TNF-alpha, IL-1, IL-6, IL-8, INF-gamma, IL-1ra, IL-10, and IL-4 cytokines, and also factors controlling the state of bone tissue, namely, osteoprotegerine (OPG), and RANK-ligand. In gingival fluid of CGP patients the increase in both pro-, and anti-inflammatory mediators with indication to Th2-deviation (decrease of INF-gamma level and elevation of IL-4 level) was observed. CGP patients exhibited in their periodontal complex marked increase of IgG, IgM, and IgA concentrations that apparently evidenced to the consequence of local polyclonal activation of B-lymphocytes. Gingival fluid of CGP patients showed the elevation of RANKL, TNF-alpha, and IL-1 levels, and the decrease in OPG concentration that could be the reason for osteoclast activation and subsequent destruction of bone tissue. In case of CGP in the zone of periodontium developed <<atypical>> inflammation that is characterized by elevated level of IL-8 and predominance of neutrophil number over the quantity of other types of leukocytes. | 18,833,135 |
[The function of gastric stump and duodenum after proximal gastric resection in patients with esophageal and gastric varicose veins dilatation]. | The authors had developed the technique of proximal gastric resection with cardiac orifice plasty. 21 patients with esophageal and varicose veins dilatation were operated on using the technique. Follow-up period came from 2 to 23 years. Results of the operation allow proximal gastric resection with cardiac orifice plasty to be considered the effective way of prevention and treatment of gastric bleedings of portal hypertension aetiology. | 18,833,147 |
[Clinical aspects of diagnostics and surgical treatment of acute primary purulent destructive pyelonephritis]. | 79 patients with the acute primary non-obstructive pyelonephritis were treated during 2003-2006. 24 (30.3%) patients were operated on with the diagnosis of acute primary purulent destructive pyelonephritis. Organopreserving operations were performed in 23 (95.8%) of patients. The early diagnostics of purulent destructive complications of pyelonephritis, using the developed diagnostic algorithm, and modified operative technique allowed to increase the rate of organopreserving operations, avoid reinterventions and decrease the risk of intraoperative complications. | 18,833,158 |
[The use of axamon in the complex rehabilitation of patients with movement disorders in the pathology of lumbar spine]. | The authors review the use of axamon in the complex rehabilitation of neurological patients with movement disorders in the pathology of lumbar spine. Axamon (ipidacrine) stimulates neuromuscular transmission and excitement conduction via nerves and smooth muscles due to the blockade of potassium channels of the excited membrane and cholinesterase inhibition. Authors studied the efficacy of complex therapy of dorsopathy of lumbar spine in 90 patients using axamon, movalis, pantogamum in different combination and manual methodics. Patient's status has been measured clinically and with several scales. The results obtained allow to conclude that the combination of axamon and pantogamum exerts the best theraupetic effect without any side symptoms. | 18,833,171 |
[Surgical tactics of obturative large bowel tumor obstruction]. | Results of Hartmann operation performed on tumor left colon part obturation in general hospitals. Results of 117 patients' treatment were analysed. The local tumor recurrence was registered in 17 (14,5%) cases, mean time between initial and reconstructive operations was 7,2 months. Results of 61 patients for whom the two-step treatment scheme (decompressive colostomy followed by the radical tumor resection and a simultaneous stoma closure) was used, are analyzed. Lethality rate was 1,6%. Second operation was performed in 58 patients in the mean time of 18,3 days after colostomy. 7 (12,1%) patients had early postoperative complications. Authors conclude that a two-step treatment protocol has advantages of higher radicality and the quality of life improvement. | 18,833,178 |
[Surgical treatment of haemorrhoids]. | The new improved modification of haemorrhoidectomy was warked out. The mucosa is dissected 0,5-0,7 sm above the node basis, it is separated sharply from the mucosa, whereupon the vascular pedicle is ligated. After cutting the haemorrhoid node off, a continuous submucosal suture is used to submerge the stump in the submucosal space. In comparison with the traditional technique, the method provides prophylaxis of bleedings and inflammatory complications; reduces the postoperative pain and dysuria. Submucosal haemorrhoidectomy facilitates the primary wound healing, early recovery of microcirculation, perceptibility and neuromuscular rectum coordination. Full recovery was achieved after 18,1+/-4,7 days after the operation. | 18,833,179 |
Zili is required for germ cell differentiation and meiosis in zebrafish. | Small RNAs exert an effect through diverse RNA interference pathways to transcriptionally or post-transcriptionally silence their targets. The Piwi-interacting RNAs (piRNAs) represent a germline-specific small RNA pathway where Piwi proteins themselves are thought to mediate piRNA biosynthesis. Here, we provide strong evidence for a piRNA amplification loop in zebrafish, in which Ziwi and Zili bind piRNAs of opposite polarity. Furthermore, we describe a function for Zili in transposon defense and germ cell differentiation, as well as a crucial function in meiosis, significantly extending the function of Piwi proteins beyond the control of transposable elements in vertebrates. | 18,833,190 |
A novel disulphide switch mechanism in Ero1alpha balances ER oxidation in human cells. | Oxidative maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is powered by Ero1 oxidases. To prevent cellular hyperoxidation, Ero1 activity can be regulated by intramolecular disulphide switches. Here, we determine the redox-driven shutdown mechanism of Ero1alpha, the housekeeping Ero1 enzyme in human cells. We show that functional silencing of Ero1alpha in cells arises from the formation of a disulphide bond-identified by mass spectrometry--between the active-site Cys(94) (connected to Cys(99) in the active enzyme) and Cys(131). Competition between substrate thiols and Cys(131) creates a feedback loop where activation of Ero1alpha is linked to the availability of its substrate, reduced protein disulphide isomerase (PDI). Overexpression of Ero1alpha-Cys131Ala or the isoform Ero1beta, which does not have an equivalent disulphide switch, leads to augmented ER oxidation. These data reveal a novel regulatory feedback system where PDI emerges as a central regulator of ER redox homoeostasis. | 18,833,192 |
Association of arterial stiffness with the angiotensin-converting enzyme gene polymorphism in healthy individuals. | Arterial stiffness is an important determinant of cardiovascular morbidity and mortality. The I/D polymorphism of angiotensin-converting enzyme (ACE) gene is associated with cardiovascular disease. However, the relationship between ACE polymorphism, arterial stiffness, and wave reflections in healthy, low-risk population has not been defined yet. The study included 282 apparently healthy, low-risk individuals (mean age 39.7 +/- 8.9 years, 178 males). Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness, while wave reflections were assessed by augmentation index (AIx) of the central pressure waveform. I/D polymorphism of the ACE gene was determined in all subjects for the prevalence of the DD, ID, and II genotype (39, 44, and 17%, respectively). C-reactive protein (CRP) levels were determined as a marker of chronic, subclinical inflammation. After adjustment for potential confounding factors, presence of D allele was associated with lower values of PWV compared to II genotype (P < 0.05), implying lower aortic stiffness for D allele carriers. There was no association between ACE genotype and wave reflections or peripheral and central systolic pressures. In apparently healthy individuals, D allele is associated with lower aortic stiffness, whereas there is no association of the ACE polymorphism with wave reflections. This finding provides new insights into the possible links between ACE gene, regulation of large artery stiffness, and has implications for cardiovascular risk. | 18,833,197 |
Night time blood pressure variability is a strong predictor for cardiovascular events in patients with type 2 diabetes. | We aimed this study to test the hypothesis that short-term blood pressure (BP) variability and abnormal patterns of diurnal BP variation, evaluated by ambulatory BP (ABP), predicts risk of incident cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM). ABP monitoring (ABPM) was performed in 300 patients with uncomplicated T2DM without known CVD and without BP medications, who were followed for 54 +/- 20 months. The relationships of different measures of BP variability, the presence of abnormal patterns of diurnal BP variation (nondipper, riser, or morning BP surge) and the standard deviations of awake and asleep ABP were determined. Cox proportional hazards models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) before and after controlling for various covariates. The mean age was 67.8 +/- 9.6 years, 48% were male, 253 (84%) had a diagnosis of hypertension, and the mean of the standard deviations of awake systolic BP/diastolic BP (SBP/DBP) were 18 +/- 6/11 +/- 4 mm Hg, and those of sleep SBP/DBP were 13 +/- 5/9 +/- 3 mm Hg. During follow-up, there were 29 cardiovascular events. In multivariable analyses, the standard deviations of sleep SBP (HR = 1.08; 95% CI, 1.01-1.16, P < 0.05) and sleep DBP (HR = 1.13; 1.04-1.23, P < 0.01) were independently associated with incident CVD. Neither the nondipper and riser patterns nor the morning BP surge were associated with incident CVD events independently of clinic and 24-h BP levels. Abnormal diurnal BP variation was not a predictor of CVD in patients with T2DM. Night time BP variability was an independent predictor of future incidence of CVD, suggesting that this measure could reflect pathophysiology of T2DM. | 18,833,198 |
A convenient, high-throughput method for enzyme-luminescence detection of dopamine released from PC12 cells. | This protocol represents a novel enzyme-luminescence method to detect dopamine sensitively and rapidly with high temporal resolution. In principle, dopamine is first oxidized with tyramine oxidase to produce H(2)O(2), and then the produced H(2)O(2) reacts with luminol to generate chemiluminescence in the presence of horseradish peroxidase (POD). We applied this method successfully to perform real-time monitoring of dopamine release from PC12 cells using a luminescence plate reader upon stimulation with several drugs (e.g., acetylcholine, bradykinin). The results indicated that the dopamine release from PC12 cells was modulated by these drugs in a way similar to that found by using several conventional analytical techniques, such as HPLC-electrochemical detector (ECD). Unlike other assays, this assay technique is simple, rapid, highly sensitive and thus useful for assessment of effects of drugs on the nervous system. The dopamine release assay takes only < or =1 h once reagent setup and culture plates' preparation are finished. | 18,833,200 |
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